DOCSLIB.ORG

Phase I Study of Epigenetic Priming with Azacitidine Prior to Standard Neoadjuvant

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Phase I Study of Epigenetic Priming with Azacitidine Prior to Standard Neoadjuvant Author Manuscript Published OnlineFirst on November 10, 2016; DOI: 10.1158/1078-0432.CCR-16-1896 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 Phase I study of epigenetic priming with azacitidine prior to standard neoadjuvant chemotherapy for patients with resectable gastric and esophageal adenocarcinoma: Evidence of tumor hypomethylation as an indicator of major histopathologic response Running Title: Neoadjuvant epigenetic priming for upper GI adenocarcinoma Bryan J. Schneider, M.D.1, Manish A. Shah, M.D.1, Kelsey Klute, M.D.1, Allyson Ocean, M.D.1, Elizabeta Popa, M.D.1, Nasser Altorki, M.D.2, Michael Lieberman, MD, Andrew Schreiner, M.D.3, Rhonda Yantiss, M.D.3, Paul J. Christos, Dr.P.H. M.S.4, Romae Palmer5, Daoqi You7, Agnes Viale, Ph.D.7, Pouneh Kermani, Ph.D. 1, Joseph M. Scandura, M.D., Ph.D.1,6 1 Division of Hematology/Oncology, Department of Internal Medicine; 2 Department of Thoracic Surgery; 3 Department of Pathology; 4 Division of Biostatistics and Epidemiology, Department of Healthcare Policy and Research; 5 Clinical Trials Office, 6 Division of Regenerative Medicine, Department of Internal Medicine; Weill Cornell Medical College, New York, New York, USA; 7Memorial Sloan-Kettering Cancer Center, New York, New York, USA. Corresponding Author: Bryan J. Schneider, M.D. C411 Med Inn Building 1500 E. Medical Center Dr, SPC 5848 Ann Arbor, MI 48019-5848 Phone: (734) 647-8921 Fax: (734) 647-8792 E-mail: [email protected] Prior Presentation: Poster presentation at ASCO Annual Meeting, Chicago, IL; May 31, 2014 Research Support: Research was partially supported by the Clinical and Translational Science Center at Weill Cornell Medical College (UL1-TR000457-06) (P.J.C), by the National Cancer Institute (CA159175) (J.M.S) and Leukemia & Lymphoma Society (J.M.S) and by the Madeline and Stephen Anbinder Clinical Scholar Award (B.J.S). Celgene provided Vidaza (5-azacitidine) for this study. Conflicts of Interest: No author reported relevant financial interests in this manuscript with the following exceptions: Dr. Allyson Ocean received honoraria from Celgene while serving on the speaker bureau for nab-paclitaxel. 1 Downloaded from clincancerres.aacrjournals.org on September 26, 2021. © 2016 American Association for Cancer Research. Author Manuscript Published OnlineFirst on November 10, 2016; DOI: 10.1158/1078-0432.CCR-16-1896 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 2 STATEMENT OF TRANSLATIONAL RELEVANCE This manuscript describes an open-label, phase I study that we performed to explore the feasibility, safety and biologic activity of epigenetic priming with 5-azacitidine prior to neoadjuvant epirubicin, oxaliplatin and capecitabine chemotherapy in patients with potentially resectable esophageal/gastric cancer. Complete response is requisite for the cure of esophageal and gastric adenocarcinoma, and this study demonstrates that it is safe to combine the epigenetic modifier, azacitidine, with full-dose, neoadjuvant, cytotoxic chemotherapy as an approach to improve complete response rates and improve survival. These findings provide the foundation for a subsequent phase II study to more clearly characterize the efficacy of epigenetic priming during neoadjuvant chemotherapy. We expect that this study defining the feasibility of epigenetic priming in gastric and esophageal adenocarcinoma will translate to therapeutic advances in more common forms of cancer since transcriptional silencing of TSGs by DNA hypermethylation is seen in most, if not all, forms of cancer. 2 Downloaded from clincancerres.aacrjournals.org on September 26, 2021. © 2016 American Association for Cancer Research. Author Manuscript Published OnlineFirst on November 10, 2016; DOI: 10.1158/1078-0432.CCR-16-1896 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 3 ABSTRACT PURPOSE Epigenetic silencing of tumor suppressor genes (TSGs) is an acquired abnormality observed in cancer and is prototypically linked to DNA methylation. We postulated that pre-treatment (priming) with 5- azacitidine would increase the efficacy of chemotherapy by reactivating TSGs. This study was conducted to identify a tolerable dose of 5-azacitidine prior to EOX (epirubicin, oxaliplatin, capecitabine) neoadjuvant chemotherapy in patients with locally-advanced esophageal/gastric adenocarcinoma (EGC). PATIENTS AND METHODS Eligible patients had untreated, locally-advanced, resectable EGC, ECOG 0-2 and adequate organ function. 5-azacitidine (V, 75mg/m2) was given subcutaneously for 3 (dose level, DL 1) or 5 (DL 2) days prior to each 21-day cycle of EOX (E 50 mg/m2, O 130 mg/m2, X 625 mg/m2 BIDx21 d). Standard 3+3 methodology guided V dose escalation. DNA methylation at control and biomarker regions was measured by digital droplet, bisulfite qPCR in tumor samples collected at baseline and at resection. RESULTS All subjects underwent complete resection of residual tumor (R0). Three of the 12 patients (25%) achieved a surgical complete response and five had partial responses. The overall response rate was 67%. The most common toxicities were gastrointestinal and hematologic. Hypomethylation of biomarker genes was observed at all dose levels and trended with therapeutic response. CONCLUSION Neoadjuvant VEOX was well-tolerated with significant clinical and epigenetic responses, with preliminary evidence that priming with V prior to chemotherapy may augment chemotherapy efficacy. 3 Downloaded from clincancerres.aacrjournals.org on September 26, 2021. © 2016 American Association for Cancer Research. Author Manuscript Published OnlineFirst on November 10, 2016; DOI: 10.1158/1078-0432.CCR-16-1896 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 4 The recommended phase II trial schedule is 5-azacitidine 75 mg/m2 for 5 days followed by EOX chemotherapy every 21 days. Key Words: Azacitidine, neoadjuvant chemotherapy, phase I, gastric cancer, esophageal cancer, adenocarcinoma, epigenetic priming 4 Downloaded from clincancerres.aacrjournals.org on September 26, 2021. © 2016 American Association for Cancer Research. Author Manuscript Published OnlineFirst on November 10, 2016; DOI: 10.1158/1078-0432.CCR-16-1896 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 5 INTRODUCTION Epigenetic silencing of tumor suppressor genes (TSGs) is commonly observed in gastroesophageal cancer and is believed to play a role in oncogenesis, metastasis and chemotherapy resistance(1-7). 5-Azacitidine (V, Vidaza) is a cytosine analog that acts as a DNA hypomethylating agent (DHA) because it cannot accept a methyl donor in the 5’position of the pyrimidine ring and depletes cellular DNA methyltransferase I (DNMT1). Reactivated expression of TSGs is commonly implicated in the clinical activity of DHAs since TSGs often regulate apoptosis, DNA repair, and checkpoint control. In vitro, DHAs can sensitize resistant cancer cells to a variety of cytotoxic agents (8-11) including the most active chemotherapies for gastroesophageal cancer (platinum agents and epirubicin)(10, 12-15). Yet this approach has been sparsely studied in clinical trials and has never been tested in EGC. We hypothesized that pre-treatment (i.e., priming) with a hypomethylating agent will sensitize the adenocarcinoma to cytotoxic therapy and increase the efficacy of neoadjuvant chemotherapy by reactivating expression of chemotherapy-sensitizing TSGs during the window of exposure to cytotoxic agents. We previously found that “epigenetic priming” using a DHA prior to intensive chemotherapy for acute myelogenous leukemia (AML) showed favorable activity without additive toxicity, and this approach is currently being tested in a large, multi-center, randomized phase II study sponsored by NCI (clinicaltrials.gov NCT00538876 and NCT01627041) (16, 17). Others have found that DHAs can be safely combined with chemotherapy for solid tumor malignancies, although experience is quite limited (18-22). We conducted an open label phase I evaluation of the feasibility, safety and biologic activity of epigenetic priming using the hypomethylating agent 5-azacitidine prior to full-dose, neoadjuvant epirubicin, oxaliplatin and capecitabine (EOX) chemotherapy in patients with surgically- resectable EGC (clinicaltrials.gov NCT01386346). Tumor DNA hypomethylation was analyzed in 5 Downloaded from clincancerres.aacrjournals.org on September 26, 2021. © 2016 American Association for Cancer Research. Author Manuscript Published OnlineFirst on November 10, 2016; DOI: 10.1158/1078-0432.CCR-16-1896 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 6 samples obtained before and following azacitidine treatment as a pharmacodynamic biomarker of epigenetic response. METHODS Eligibility Adult patients (age ≥ 18) with untreated, histologically confirmed locoregional adenocarcinoma of the intrathoracic esophagus, gastroesophageal junction or stomach were eligible if they were deemed potentially resectable by the surgeon. Eligible patients had Zubrod performance status (PS) of 0-2, no baseline hematopoietic deficiencies (absolute neutrophil count (ANC) ≥ 1500/mm3, platelet count ≥ 100,000/mm3) and adequate organ function (serum creatinine ≤ 1.5X the institutional upper limit of normal (ULN), total bilirubin ≤ 1.5X ULN, and AST/ALT ≤ 2.0X ULN). Patients were ineligible if they
Load more

Recommended publications
  • Epigenetics in Clinical Practice: the Examples of Azacitidine and Decitabine in Myelodysplasia and Acute Myeloid Leukemia
    Leukemia (2013) 27, 1803–1812 & 2013 Macmillan Publishers Limited All rights reserved 0887-6924/13 www.nature.com/leu SPOTLIGHT REVIEW Epigenetics in clinical practice: the examples of azacitidine and decitabine in myelodysplasia and acute myeloid leukemia EH Estey Randomized trials have clearly demonstrated that the hypomethylating agents azacitidine and decitabine are more effective than ‘best supportive care’(BSC) in reducing transfusion frequency in ‘low-risk’ myelodysplasia (MDS) and in prolonging survival compared with BSC or low-dose ara-C in ‘high-risk’ MDS or acute myeloid leukemia (AML) with 21–30% blasts. They also appear equivalent to conventional induction chemotherapy in AML with 420% blasts and as conditioning regimens before allogeneic transplant (hematopoietic cell transplant, HCT) in MDS. Although azacitidine or decitabine are thus the standard to which newer therapies should be compared, here we discuss whether the improvement they afford in overall survival is sufficient to warrant a designation as a standard in treating individual patients. We also discuss pre- and post-treatment covariates, including assays of methylation to predict response, different schedules of administration, combinations with other active agents and use in settings other than active disease, in particular post HCT. We note that rational development of this class of drugs awaits delineation of how much of their undoubted effect in fact results from hypomethylation and reactivation of gene expression. Leukemia (2013) 27, 1803–1812; doi:10.1038/leu.2013.173
    [Show full text]
  • Clinical Implications of Epigenetics Research
    Clinical Implications of Epigenetics Research Nita Ahuja MD FACS Associate Professor of Surgery, Oncology and Urology Vice Chair of Academic Affairs Chief: Section of GI Oncology & BME Services Epigenetics: Our Software August 1, 2014 2 What is Epigenetics? . Heritable changes in gene expression not due to changes in the DNA sequence . DNA methylation . Chromatin structure or histone code . Role in normal and pathological processes, such as aging, mental health, and cancer, among others. DNA Methylation changes in Neoplasia Normal 1 2 3 Cancer 1 2 3 Epigenetic changes in Neoplasia Normal 1 2 3 AcK9 AcK9 MeK9 MeK9 MeK4 MeK4 MeK27 MeK27 Cancer 1 2 3 MeK9 MeK9 MeK9 MeK9 MeK9 MeK27 MeK27 MeK27 MeK27 MeK27 ?? Epigenetic changes in Neoplasia HATs HDemethylases Normal 1 2 3 AcK9 AcK9 MeK9 MeK9 MeK4 MeK4 MeK27 Aging MeK27 Inflammation HDACs H MTases Cancer 1 2 3 MeK9 MeK9 MeK9 MeK9 MeK9 MeK27 MeK27 MeK27 MeK27 MeK27 ?? Ahuja et. al. Cancer Res. 1998 Issa et. al Cancer Res 2001 Cancer Epigenetics: ApplicationsProtein Repressor proteins RNA (MBD, HDAC) DNA Promoter Gene Cancer Marker for Prognostic Reversal of Gene Silencing Molecular Staging And Predictive Epigenetic Early Detection Biomarkers Therapy Colon Cancer Functional Methylome • Each colon cancer has ~150 to 450 DAC methylated genes/tumor TSA Yellow spots indicate genes from DKO cells with 2 fold changes and above. Green spots indicate experimentally verified genes. Red spots indicate those that did not verify. Blue spots indicate the location of the 11 guide genes used in this study. Schuebel
    [Show full text]
  • Bronchial Biopsy Specimen As a Surrogate for DNA Methylation Analysis in Inoperable Lung Cancer
    Um et al. Clinical Epigenetics (2017) 9:131 DOI 10.1186/s13148-017-0432-5 RESEARCH Open Access Bronchial biopsy specimen as a surrogate for DNA methylation analysis in inoperable lung cancer Sang-Won Um1†, Hong Kwan Kim2†, Yujin Kim3, Bo Bin Lee3, Dongho Kim3, Joungho Han4, Hojoong Kim1, Young Mog Shim2 and Duk-Hwan Kim3,5* Abstract Background: This study was aimed at understanding whether bronchial biopsy specimen can be used as a surrogate for DNA methylation analysis in surgically resected lung cancer. Methods: A genome-wide methylation was analyzed in 42 surgically resected tumor tissues, 136 bronchial washing, 12 sputum, and 8 bronchial biopsy specimens using the Infinium HumanMethylation450 BeadChip, and models for prediction of lung cancer were evaluated using TCGA lung cancer data. Results: Four thousand seven hundred and twenty-six CpGs (P < 1.0E-07) that were highly methylated in tumor tissues were identified from 42 lung cancer patients. Ten CpGs were selected for prediction of lung cancer. Genes including the 10 CpGs were classified into three categories: (i) transcription (HOXA9, SOX17, ZNF154, HOXD13); (ii) cell signaling (HBP1, SFRP1, VIPR2); and (iii) adhesion (PCDH17, ITGA5, CD34). Three logistic regression models based on the 10 CpGs classified 897 TCGA primary lung tissues with a sensitivity of 95.0~97.8% and a specificity of 97.4~98. 7%. However, the classification performance of the models was very poor in bronchial washing samples: the area under the curve (AUC) was equal to 0.72~0.78. The methylation levels of the 10 CpGs in bronchial biopsy were not significantly different from those in surgically resected tumor tissues (P > 0.05, Wilcoxon rank-sum test).
    [Show full text]
  • Phase I Study of Epigenetic Priming With
    Published OnlineFirst November 10, 2016; DOI: 10.1158/1078-0432.CCR-16-1896 Cancer Therapy: Clinical Clinical Cancer Research Phase I Study of Epigenetic Priming with Azacitidine Prior to Standard Neoadjuvant Chemotherapy for Patients with Resectable Gastric and Esophageal Adenocarcinoma: Evidence of Tumor Hypomethylation as an Indicator of Major Histopathologic Response Bryan J. Schneider1, Manish A. Shah1, Kelsey Klute1, Allyson Ocean1, Elizabeta Popa1, Nasser Altorki2, Michael Lieberman3, Andrew Schreiner4, Rhonda Yantiss4, Paul J. Christos5, Romae Palmer6, Daoqi You7, Agnes Viale7, Pouneh Kermani1, and Joseph M. Scandura1,8 Abstract Purpose: Epigenetic silencing of tumor suppressor genes (TSG) by digital droplet, bisulfite qPCR in tumor samples collected at is an acquired abnormality observed in cancer and is prototyp- baseline and at resection. ically linked to DNA methylation. We postulated that pretreat- Results: All subjects underwent complete resection of residual ment (priming) with 5-azacitidine would increase the efficacy of tumor (R0). Three of the 12 patients (25%) achieved a surgical chemotherapy by reactivating TSGs. This study was conducted to complete response and 5 had partial responses. The overall identify a tolerable dose of 5-azacitidine prior to EOX (epirubicin, response rate was 67%. The most common toxicities were gas- oxaliplatin, capecitabine) neoadjuvant chemotherapy in patients trointestinal and hematologic. Hypomethylation of biomarker with locally advanced esophageal/gastric adenocarcinoma genes was observed at all dose levels and trended with therapeutic (EGC). response. Experimental Design: Eligible patients had untreated, locally Conclusions: Neoadjuvant VEOX was well-tolerated with advanced, resectable EGC, ECOG 0–2, and adequate organ func- significant clinical and epigenetic responses, with preliminary tion.
    [Show full text]
  • Epigenetic Research in Stem Cell Bioengineering—Anti-Cancer Therapy, Regenerative and Reconstructive Medicine in Human Clinical Trials
    cancers Review Epigenetic Research in Stem Cell Bioengineering—Anti-Cancer Therapy, Regenerative and Reconstructive Medicine in Human Clinical Trials Claudia Dompe 1,2, Krzysztof Janowicz 2,3, Greg Hutchings 2,3, Lisa Moncrieff 1,2, Maurycy Jankowski 3 , Mariusz J. Nawrocki 3 , Małgorzata Józkowiak 4, Paul Mozdziak 5 , Jim Petitte 6 , Jamil A. Shibli 7 , Marta Dyszkiewicz-Konwi ´nska 3,8 , Małgorzata Bruska 3, Hanna Piotrowska-Kempisty 4, Bartosz Kempisty 1,3,9,10,* and Michał Nowicki 1 1 Department of Histology and Embryology, Poznan University of Medical Sciences, 60-781 Poznan, Poland; [email protected] (C.D.); l.moncrieff[email protected] (L.M.); [email protected] (M.N.) 2 The School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen AB25 2ZD, UK; [email protected] (K.J.); [email protected] (G.H.) 3 Department of Anatomy, Poznan University of Medical Sciences, 60-781 Poznan, Poland; [email protected] (M.J.); [email protected] (M.J.N.); [email protected] (M.D.-K.); [email protected] (M.B.) 4 Department of Toxicology, Poznan University of Medical Sciences, 61-631 Poznan, Poland; [email protected] (M.J.); [email protected] (H.P.-K.) 5 Physiology Graduate Program, North Carolina State University, Raleigh, NC 27695, USA; [email protected] 6 Prestage Department of Poultry Science, North Carolina State University, Raleigh, NC 27695, USA; [email protected] 7 Department of Periodontology and Oral Implantology, Dental Research Division, University of Guarulhos, São
    [Show full text]
  • Epigenetic Priming in Drug Addiction
    Epigenetic Priming in Drug Addiction PHILIPP MEWS,DEENA M. WALKER, AND ERIC J. NESTLER Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA Correspondence: [email protected]; [email protected] Drug addiction is a chronic relapsing brain disorder that is characterized by compulsive drug seeking and continued use despite negative outcomes. Current pharmacological therapies target neuronal receptors or transporters upon which drugs of abuse act initially, yet these treatments remain ineffective for most individuals and do not prevent disease relapse after abstinence. Drugs of abuse, in addition to their acute effects, cause persistent plasticity after repeated use, involving dysregulated gene expression in the brain’s reward regions, which are thought to mediate the persistent behavioral abnormalities that characterize addiction. Emerging evidence implicates epigenetic priming as a key mechanism that underlies the long-lasting alterations in neuronal gene regulation, which can remain latent until triggered by re-exposure to drug-associated stimuli or the drug itself. Thus, to effectively treat drug addiction, we must identify the precise epigenetic mechanisms that establish and preserve the drug- induced pathology of the brain reward circuitry. TRANSCRIPTIONAL PRIMING AS A DISEASE long faded (Walker et al. 2015). Permanent (or at least MECHANISM IN DRUG ADDICTION highly stable) changes in neuronal chromatin structure are assumed to underlie such latent dysregulation of tran- Drug addiction is a debilitating neuropsychiatric dis- scription, which is referred to as gene “priming” and order with severe health, financial, and societal conse- “desensitization” (Robison and Nestler 2011; Bastle and quences (Leshner 1997).
    [Show full text]
  • Chidamide, Decitabine, Cytarabine, Aclarubicin, and Granulocyte Colony
    Wang et al. Clinical Epigenetics (2020) 12:132 https://doi.org/10.1186/s13148-020-00923-4 RESEARCH Open Access Chidamide, decitabine, cytarabine, aclarubicin, and granulocyte colony- stimulating factor (CDCAG) in patients with relapsed/refractory acute myeloid leukemia: a single-arm, phase 1/2 study Lixin Wang1,2†, Jianmin Luo3†, Guofeng Chen4,5,6†, Meiyun Fang7, Xudong Wei8, Yinghua Li9, Zhuogang Liu10, Yin Zhang11, Sujun Gao12, Jianliang Shen2, Xin Wang13, Xiaoning Gao6, Wei Zhou5, Yigai Ma14, Hui Liu15, Xinquan Li16, Linhua Yang17, Kai Sun11 and Li Yu1,6* Abstract Background: Epigenetic mechanisms play an important role in the chemoresistance of acute myeloid leukemia (AML). The clinical response to epigenetic modifier-based chemotherapy in patients with relapsed/refractory AML (r/ r AML) is unclear. This multicenter clinical trial evaluated the safety and efficacy of epigenetic modifiers (chidamide and decitabine) in combination with aclarubicin, cytarabine, and granulocyte colony-stimulating factor (G-CSF) in patients with r/r AML. Results: Adult patients with r/r AML were treated with chidamide, decitabine, cytarabine, aclarubicin, and G-CSF (CDCAG). The primary measures were overall response (OR), overall survival (OS), and safety. Next-generation sequencing was performed to analyze the correlation between gene mutations and response. A total of 93 patients with r/r AML were enrolled. Overall, 24 patients had a complete remission (CR) and 19 patients achieved CR with incomplete blood count recovery (CRi). The overall response rate (ORR) was 46.2%. The overall survival of these 43 patients who achieved CR/CRi was significantly longer than that of patients who failed to achieve remission (563 vs 152 days, P < 0.0001).
    [Show full text]
  • Low-Dose DNA Demethylating Therapy Induces Reprogramming of Diverse
    Takeshima et al. Clinical Epigenetics (2020) 12:142 https://doi.org/10.1186/s13148-020-00937-y RESEARCH Open Access Low-dose DNA demethylating therapy induces reprogramming of diverse cancer- related pathways at the single-cell level Hideyuki Takeshima1†, Yukie Yoda1,2†, Mika Wakabayashi1, Naoko Hattori1, Satoshi Yamashita1 and Toshikazu Ushijima1* Abstract Background: Epigenetic reprogramming using DNA demethylating drugs is a promising approach for cancer therapy, but its efficacy is highly dependent on the dosing regimen. Low-dose treatment for a prolonged period shows a remarkable therapeutic efficacy, despite its small demethylating effect. Here, we aimed to explore the mechanisms of how such low-dose treatment shows this remarkable efficacy by focusing on epigenetic reprograming at the single-cell level. Methods: Expression profiles in HCT116 cells treated with decitabine (DAC) were analyzed by single-cell RNA- sequencing (scRNA-seq). Functional consequences and DNA demethylation at the single-cell level were analyzed using cloned HCT116 cells after DAC treatment. Results: scRNA-seq revealed that DAC-treated cells had highly diverse expression profiles at the single-cell level, and tumor-suppressor genes, endogenous retroviruses, and interferon-stimulated genes were upregulated in random fractions of cells. DNA methylation analysis of cloned HCT116 cells revealed that, while only partial reduction of DNA methylation levels was observed in bulk cells, complete demethylation of specific cancer-related genes, such as cell cycle regulation, WNT pathway, p53 pathway, and TGF-β pathway, was observed, depending upon clones. Functionally, a clone with complete demethylation of CDKN2A (p16) had a larger fraction of cells with tetraploid than parental cells, indicating induction of cellular senescence due to normalization of cell cycle regulation.
    [Show full text]
  • The Key Role of DNA Methylation and Histone Acetylation in Epigenetics of Atherosclerosis
    J Lipid Atheroscler. 2020 Sep;9(3):419-434 Journal of https://doi.org/10.12997/jla.2020.9.3.419 Lipid and pISSN 2287-2892·eISSN 2288-2561 Atherosclerosis Review The Key Role of DNA Methylation and Histone Acetylation in Epigenetics of Atherosclerosis Han-Teo Lee ,1,2,* Sanghyeon Oh ,1,2,* Du Hyun Ro ,1,2,3,* Hyerin Yoo ,1,2 Yoo-Wook Kwon 4,5 1Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science, Seoul National University, Seoul, Korea 2Interdisciplinary Program in Stem Cell Biology, Graduate School of Medicine, Seoul National University, Seoul, Korea 3Department of Orthopedic Surgery, Seoul National University Hospital, Seoul, Korea 4Strategic Center of Cell and Bio Therapy for Heart, Diabetes & Cancer, Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea Received: May 8, 2020 5Department of Medicine, College of Medicine, Seoul National University, Seoul, Korea Revised: Sep 14, 2020 Accepted: Sep 15, 2020 Correspondence to ABSTRACT Yoo-Wook Kwon Biomedical Research Institute, Seoul National Atherosclerosis, which is the most common chronic disease of the coronary artery, constitutes University Hospital, 103 Daehak-ro, Jongno- a vascular pathology induced by inflammation and plaque accumulation within arterial vessel gu, Seoul 03080, Korea. E-mail: [email protected] walls. Both DNA methylation and histone modifications are epigenetic changes relevant for atherosclerosis. Recent studies have shown that the DNA methylation and histone *Han-Teo Lee, Sanghyeon Oh and Du Hyun Ro modification systems are closely interrelated and mechanically dependent on each other. contributed equally to this work. Herein, we explore the functional linkage between these systems, with a particular emphasis Copyright © 2020 The Korean Society of Lipid on several recent findings suggesting that histone acetylation can help in targeting DNA and Atherosclerosis.
    [Show full text]
  • Epigenetic Priming Restores the HLA Class-I Antigen Processing
    www.nature.com/scientificreports OPEN Epigenetic priming restores the HLA class-I antigen processing machinery expression in Merkel cell Received: 24 January 2017 Accepted: 12 April 2017 carcinoma Published: xx xx xxxx Cathrin Ritter1,2,3, Kaiji Fan1,4, Annette Paschen5, Sine Reker Hardrup6, Soldano Ferrone7, Paul Nghiem 8, Selma Ugurel5, David Schrama9 & Jürgen C. Becker 1,2,3,5 Merkel cell carcinoma (MCC) is a rare and aggressive, yet highly immunogenic skin cancer. The latter is due to its viral or UV-associated carcinogenesis. For tumor progression MCC has to escape the host’s immuno-surveillance, e.g. by loss of HLA class-I expression. Indeed, a reduced HLA class-I expression was observed in MCC tumor tissues and MCC cell lines. This reduced HLA class-I surface expression is caused by an impaired expression of key components of the antigen processing machinery (APM), including LMP2 and LMP7 as well as TAP1 and TAP2. Notably, experimental provisions of HLA class-I binding peptides restored HLA class-I surface expression on MCC cells. Silencing of the HLA class-I APM is due to histone deacetylation as inhibition of histone deacetylases (HDACs) not only induced acetylation of histones in the respective promoter regions but also re-expression of APM components. Thus, HDAC inhibition restored HLA class-I surface expression in vitro and in a mouse xenotransplantation model. In contrast to re-induction of HLA class-I by interferons, HDAC inhibitors did not interfere with the expression of immuno-dominant viral proteins. In summary, restoration of HLA class-I expression on MCC cells by epigenetic priming is an attractive approach to enhance therapies boosting adaptive immune responses.
    [Show full text]
  • Epigenetics of Myelodysplastic Syndromes
    Leukemia (2014) 28, 497–506 & 2014 Macmillan Publishers Limited All rights reserved 0887-6924/14 www.nature.com/leu SPOTLIGHT REVIEW Epigenetics of myelodysplastic syndromes R Itzykson1,2,3 and P Fenaux1,2,4 Myelodysplastic syndromes (MDS) are clonal diseases of the elderly characterized by chronic cytopenias, dysplasia and a variable risk of progression to acute myeloid leukemia (AML). Aberrant methylation of tumor-suppressor gene promoters has been established for many years and recently tracked to the most immature cells of MDS, suggesting that these alterations are drivers of MDS pathogenesis. In recent years, recurrent somatic mutations in genes encoding proteins involved in DNA methylation and demethylation and in covalent histone modifications have been reported in myeloid malignancies, including MDS. Whole-genome epigenetic profiles of MDS are also emerging. In parallel with these advances in the molecular pathogenesis of MDS, clinical trials have established hypomethylating agents (HMAs) as the mainstay of therapy in the advanced forms of the disease. In this review, we summarize the current understanding of the molecular machinery involved in epigenetic regulation, discuss how epigenetic alterations arise in MDS and contribute to its pathogenesis and then discuss the mode of action of HMAs in MDS. Leukemia (2014) 28, 497–506; doi:10.1038/leu.2013.343 Keywords: epigenetics; myelodysplastic syndromes; methylation; histone INTRODUCTION number of animal models and human cell lines of MDS, most The notion of ‘epigenetics’ refers to all the information transmitted progresses have come from the study of primary patient samples. through cell division that is not encoded in the DNA sequence. In this Spotlight review, we summarize the current under- However, it is generally used in a restrictive sense as information standing of the molecular machinery involved in epigenetic governing transcription regulation not coded in the DNA regulation, discuss how epigenetic alterations arise in MDS and sequence.
    [Show full text]
  • From Circuits to Chromatin: the Emerging Role of Epigenetics in Mental Health
    The Journal of Neuroscience, 0, 2021 • 00(00):000 • 1 Symposium/Mini-symposium From Circuits to Chromatin: The Emerging Role of Epigenetics in Mental Health Philipp Mews,1 Erin S. Calipari,2 Jeremy Day,3 Mary Kay Lobo,4 Timothy Bredy,5 and Ted Abel6 1Friedman Brain Institute, Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York 10129, 2Departments of Pharmacology, Molecular Physiology and Biophysics, Psychiatry and Behavioral Sciences; Vanderbilt Center for Addiction Research; Vanderbilt Brain Institute, Vanderbilt University, Nashville, Tennessee 37323, 3Department of Neurobiology, McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, Alabama 35294, 4Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland 21201, 5Queensland Brain Institute, University of Queensland, Brisbane, 4072, Australia, and 6Department of Neuroscience and Pharmacology, Iowa Neuroscience Institute, University of Iowa, Iowa City, Iowa 52242 A central goal of neuroscience research is to understand how experiences modify brain circuits to guide future adaptive behavior. In response to environmental stimuli, neural circuit activity engages gene regulatory mechanisms within each cell. This activity-dependent gene expression is governed, in part, by epigenetic processes that can produce persistent changes in both neural circuits and the epigenome itself. The complex interplay between circuit activity and neuronal gene regulation is vital to learning and memory, and, when disrupted, is linked to debilitating psychiatric conditions, such as substance use dis- order. To develop clinical treatments, it is paramount to advance our understanding of how neural circuits and the epige- nome cooperate to produce behavioral adaptation. Here, we discuss how new genetic tools, used to manipulate neural circuits and chromatin, have enabled the discovery of epigenetic processes that bring about long-lasting changes in behavior relevant to mental health and disease.
    [Show full text]