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Epigenetic Silencing of Mirna-338-5P and Mirna-421

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Epigenetic Silencing of Mirna-338-5P and Mirna-421 Published OnlineFirst December 26, 2018; DOI: 10.1158/1078-0432.CCR-18-3230 Translational Cancer Mechanisms and Therapy Clinical Cancer Research Epigenetic Silencing of miRNA-338-5p and miRNA-421 Drives SPINK1-Positive Prostate Cancer Vipul Bhatia1, Anjali Yadav1, Ritika Tiwari1, Shivansh Nigam1, Sakshi Goel1, Shannon Carskadon2, Nilesh Gupta3, Apul Goel4, Nallasivam Palanisamy2, and Bushra Ateeq1 Abstract Purpose: Serine peptidase inhibitor, Kazal type-1 (SPINK1) DNA immunoprecipitation were performed on prostate overexpression defines the second most recurrent and aggres- cancer cell lines and patients' specimens. sive prostate cancer subtype. However, the underlying molec- Results: We established a critical role of miRNA-338-5p/- ular mechanism and pathobiology of SPINK1 in prostate 421 in posttranscriptional regulation of SPINK1. Ectopic cancer remains largely unknown. expression of miRNA-338-5p/-421 in SPINK1-positive cells Experimental Design: miRNA prediction tools were abrogates oncogenic properties including cell-cycle progres- employed to examine the SPINK1-30UTR for miRNA bind- sion, stemness, and drug resistance, and shows reduced tumor ing. Luciferase reporter assays were performed to confirm burden and distant metastases in a mouse model. Importantly, the SPINK1-30UTR binding of shortlisted miR-338-5p/ we show that patients with SPINK1-positive prostate cancer miR-421. Furthermore, miR-338-5p/-421–overexpressing exhibit increased EZH2 expression, suggesting its role in cancer cells (SPINK1-positive) were evaluated for onco- epigenetic silencing of miRNA-338-5p/-421. Furthermore, genic properties using cell-based functional assays and a presence of CpG dinucleotide DNA methylation marks on mouse xenograft model. Global gene expression profiling the regulatory regions of miR-338-5p/-421 in SPINK1-positive was performed to unravel the biological pathways altered prostate cancer cells and patients' specimens confirms epige- by miR-338-5p/-421. IHC and RNA in situ hybridization netic silencing. were carried out on prostate cancer patients' tissue micro- Conclusions: Our findings revealed that miRNA-338-5p/- array for SPINK1 and EZH2 expression, respectively. 421 are epigenetically silenced in SPINK1-positive prostate Chromatin immunoprecipitation assay was performed cancer, although restoring the expression of these miRNAs to examine EZH2 occupancy on the miR-338-5p/-421– using epigenetic drugs or synthetic mimics could abrogate regulatory regions. Bisulfite sequencing and methylated SPINK1-mediated oncogenesis. Introduction with this disease (1–3). Majority of these patients harbor gene rearrangements between members of the E26 transformation– Prostate cancer is characterized by extensive molecular hetero- specific(ETS) transcription factor family and the androgen-reg- geneity and varied clinical outcomes (1). Multiple molecular ulated transmembrane protease serine 2 (TMPRSS2), most recur- subtypes involving recurrent genetic rearrangements, DNA copy rent (50%) being TMPRSS2-ERG, involving the v-ets erythro- number alterations, and somatic mutations have been associated blastosis virus E26-oncogene homolog (ERG; refs. 3, 4). The TMPRSS2-ERG–encoded ERG transcription factor is known to drive cell invasion and metastases, DNA damage in vitro, and focal 1Molecular Oncology Lab, Department of Biological Sciences and Bioengineer- precancerous prostatic intraepithelial neoplasia (PIN) lesions in ing, Indian Institute of Technology Kanpur, Kanpur, Uttar Pradesh, India. 2Vatti- transgenic mice (5, 6). kuti Urology Institute, Department of Urology, Henry Ford Health System, While TMPRSS2-ERG fusion forms the most frequent molec- 3 Detroit, Michigan. Department of Pathology, Henry Ford Health System, ular subtype, a significant subset of ETS-negative (–) prostate 4 Detroit, Michigan. Department of Urology, King George's Medical University, cancer show overexpression of serine peptidase inhibitor, Kazal Lucknow, Uttar Pradesh, India. type-1 (SPINK1) in approximately 10%–15% of the total patients Note: Supplementary data for this article are available at Clinical Cancer with prostate cancer, a distinct subtype defined by overall higher Research Online (http://clincancerres.aacrjournals.org/). Gleason score, shorter progression-free survival, and biochemical V. Bhatia and A. Yadav contributed equally to this article. recurrence (7–9). SPINK1 promotes cell proliferation and inva- Corresponding Author: Bushra Ateeq, Molecular Oncology Lab, Department of sion through autocrine/paracrine signaling and mediates its onco- Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, genic effects, in part, through EGFR interaction by activating Kanpur, Uttar Pradesh 208016, India. Phone: 91-512-259-4083; Fax: 91-512-259- downstream signaling. Monoclonal EGFR antibody administered 4010; E-mail: [email protected] in SPINK1-positive xenografted mice showed only a marginal doi: 10.1158/1078-0432.CCR-18-3230 decrease in tumor burden, suggesting involvement of EGFR- Ó2018 American Association for Cancer Research independent oncogenic pathways (10). www.aacrjournals.org OF1 Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst December 26, 2018; DOI: 10.1158/1078-0432.CCR-18-3230 Bhatia et al. Translational Relevance Materials and Methods Human prostate cancer specimens We establish a regulatory model involving the functional Fresh-frozen prostate cancer specimens used in this study interplay between SPINK1, miRNA-338-5p/miRNA-421, were procured from King George's Medical University (KGMU, and EZH2, thereby revealing hitherto unknown mechanism Lucknow, India). Clinical specimens were collected after of SPINK1 upregulation in SPINK1-positive prostate cancer obtaining written informed consent and institutional review subtype. Our findings provide a strong rationale for the board approvals from KGMU and Indian Institute of Technol- development of potential therapeutic strategies for SPINK1- ogy Kanpur (Kanpur, India). A total of 20 prostate cancer positive malignancies. We demonstrate that restoring specimens were selected for this study based on SPINK1 and miRNA-338-5p/miRNA-421 expression using epigenetic TMPRSS2-ERG status, confirmed by qPCR, IHC, and FISH (4). drugs, including DNA methyltransferase (DNMT) inhibitors Tissue microarrays (TMA) comprising prostate cancer speci- in combination with histone deacetylase (HDAC) or histone mens (n ¼ 238) were obtained from Department of Pathology, lysine methyltransferase (HKMT) inhibitors or miRNA syn- Henry Ford Health System (Detroit, MI), after getting written thetic mimics in SPINK1-positive prostate cancer, abrogates informed consent and institutional review board approval. All SPINK1-mediated oncogenicity. The major findings of this patients' specimens used in this study were collected in accor- study will not only advance the prostate cancer field, but dance with the Declaration of Helsinki. TMAs were stained for also be valuable for treatment and disease management of SPINK1 and EZH2 by performing IHC and RNA in situ hybrid- other SPINK1-positive malignancies. ization (RNA-ISH), respectively. Mouse xenograft studies For mouse xenograft studies, 5- to 6-week-old NOD.CB17- scid Although, genomic events such as gene rearrangements and Prkdc /J (NOD/SCID) male mice (Jackson Laboratory) were n ¼ somatic mutations constitute most recurrent oncogenic aberra- randomized into three groups ( 8 for each experimental tions,manycouldalsobeattributedtoepigeneticalterations. condition). All procedures involving mice were approved by Earlier studies have shown that aberrant expression of enhancer the Committee for the Purpose of Control and Supervision of of zeste homolog 2 (EZH2) owing to genomic loss of miRNA- Experiments on Animals (CPCSEA) and conform to all regu- 101 (11) or hypermethylation of miR-26a (12) constitutes a latory standards of the Institutional Animal Ethics Committee common regulatory mechanism across several solid cancers. of the Indian Institute of Technology Kanpur. Detailed meth- EZH2, being the key component of the polycomb-repressive odology of the xenograft studies is provided in the Supple- complex 2 (PRC2) mediates trimethylation on the histone 3 mentary Methods and Supplementary Table S1. lysine 27 (H3K27me3), leading to gene silencing (13). How- 0 ever, phosphorylated form of EZH2 is known to switch its miRNA 3 UTR SPINK1 luciferase reporter assay 0 0 function from polycomb repressor to transcriptional coactiva- Full-length SPINK1 3 untranslated region (3 UTR) wild- tor of androgen receptor in castration-resistant prostate cancers type and mutant with altered residues in the binding sites of (CRPC; ref. 14). Moreover, recent studies have shown PRC2 miR-338-5p and miR-421 was cloned in Firefly/Renilla Dual- epigenetically suppresses the expression of several tumor-sup- Luciferase reporter vector pEZX-MT01 (GeneCopoeia). Cells pressive miRNAs such as, miR-181a/b, miR-200b/c, and miR- were seeded in a 24-well plate at 30%–40% confluency and 203, while these miRNAs in turn directly target PRC1 members, cotransfected with 30 pmol of miRNA mimics along with 25 ng namely BMI1 and RING2, thereby reinforcing the repressive of pEZX-MT01 constructs using Lipofectamine RNAiMax (Invi- molecular circuitry (15). trogen). Luciferase assay was performed using Dual-Glo Lucif- Although overexpression of SPINK1 forms the second most erase Assay (Promega) 24 hours after the second transfection. prevalent
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