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Vural et al. Clin Epigenet (2021) 13:49 https://doi.org/10.1186/s13148-021-01026-4 RESEARCH Open Access Association of expression of epigenetic molecular factors with DNA methylation and sensitivity to chemotherapeutic agents in cancer cell lines Suleyman Vural1, Alida Palmisano1,2 , William C. Reinhold3, Yves Pommier3, Beverly A. Teicher4 and Julia Krushkal1* Abstract Background: Altered DNA methylation patterns play important roles in cancer development and progression. We examined whether expression levels of genes directly or indirectly involved in DNA methylation and demethylation may be associated with response of cancer cell lines to chemotherapy treatment with a variety of antitumor agents. Results: We analyzed 72 genes encoding epigenetic factors directly or indirectly involved in DNA methylation and demethylation processes. We examined association of their pretreatment expression levels with methylation beta- values of individual DNA methylation probes, DNA methylation averaged within gene regions, and average epige- nome-wide methylation levels. We analyzed data from 645 cancer cell lines and 23 cancer types from the Cancer Cell Line Encyclopedia and Genomics of Drug Sensitivity in Cancer datasets. We observed numerous correlations between expression of genes encoding epigenetic factors and response to chemotherapeutic agents. Expression of genes encoding a variety of epigenetic factors, including KDM2B, DNMT1, EHMT2, SETDB1, EZH2, APOBEC3G, and other genes, was correlated with response to multiple agents. DNA methylation of numerous target probes and gene regions was associated with expression of multiple genes encoding epigenetic factors, underscoring complex regulation of epigenome methylation by multiple intersecting molecular pathways. The genes whose expression was associated with methylation of multiple epigenome targets encode DNA methyltransferases, TET DNA methylcytosine dioxyge- nases, the methylated DNA-binding protein ZBTB38, KDM2B, SETDB1, and other molecular factors which are involved in diverse epigenetic processes afecting DNA methylation. While baseline DNA methylation of numerous epigenome targets was correlated with cell line response to antitumor agents, the complex relationships between the overlap- ping efects of each epigenetic factor on methylation of specifc targets and the importance of such infuences in tumor response to individual agents require further investigation. Conclusions: Expression of multiple genes encoding epigenetic factors is associated with drug response and with DNA methylation of numerous epigenome targets that may afect response to therapeutic agents. Our fndings sug- gest complex and interconnected pathways regulating DNA methylation in the epigenome, which may both directly and indirectly afect response to chemotherapy. *Correspondence: [email protected] 1 Biometric Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, 9609 Medical Center Dr., Rockville, MD 20850, USA Full list of author information is available at the end of the article © The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Vural et al. Clin Epigenet (2021) 13:49 Page 2 of 23 Keywords: DNA methylation, Gene expression, Epigenetic analysis, Cancer drug treatment Background TRIM28 (KAP1), SETDB1, DNMT3L, EED, EZH2, Cancer cells acquire multiple epigenomic alterations, SUZ12, and ZSCAN4 are involved in regulation, de novo including aberrant DNA methylation and DNA hydrox- methylation, and/or maintenance of imprinted regions ymethylation of genes and genome regions, loss or gain and/or afect DNA methylation in embryonic stem cells of imprinting and allele switching of imprinted loci, and [18, 27, 31–36]. global DNA hypomethylation [1–6]. Epigenetic changes While many GMDs are involved in methylation in malignant cells result in transcriptional and post- or demethylation of 5-mC, MGMT demethylates transcriptional rewiring, infuencing cell cycle, growth, O6-methylguanine (O6-meG) lesions and removes and proliferation. Epigenetic dysregulation in tumors O6-alkyl adducts, whereas ALKBH2 and ALKBH3 dem- leads to silencing of tumor suppressor genes and of genes ethylate DNA via removal of 1-methyladenine (N 1-meA) involved in DNA repair, activates oncogene expres- and 3-methylcytosine (N3-meC) [37–39]. sion, alters gene function, afects transcriptional regula- A number of epigenetic factors have complex and tory networks, and increases genome instability [1, 4, intertwined roles afecting DNA methylation. Tere is an 6–11]. Global DNA hypomethylation of malignant cells extensive cross-talk among the DNA methylation, dem- has been associated with tumor evasion of the immune ethylation, and histone modifcation pathways in germ response [12]. line, embryonic stem, normal somatic, and malignant Many epigenetic factors directly or indirectly dynami- cells [26, 27, 31, 35, 40–42]. DNA methylation is infu- cally infuence genome region-specifc or global DNA enced by histone modifcations, and histone methylation methylation in the germ line, embryonic, or somatic and acetylation marks directly afect DNMT localization, adult cells (Additional fle 1: Table S1). Below, we refer to binding, and activities [27, 35, 40, 43]. Specifc GMD their genes as GMDs (genes afecting DNA methylation roles in DNA methylation and demethylation and exam- or demethylation). Products of the DNA methyltrans- ples of their interactions are presented in Additional ferase (DNA 5′ cytosine-methyltransferase, or DNMT) fle 1: Table S1 and accompanying text. genes DNMT1, DNMT3A and DNMT3B are directly GMD components may directly or indirectly afect involved in DNA methylation. Products of TET methyl- sensitivity of cancer cells to treatment. DNMTs are cytosine dioxygenase genes (TET1, TET2 and TET3) and directly inhibited by DNA hypomethylating agents, products of AICDA (AID) and APOBEC, TDG, MBD4, while other antitumor agents target additional GMD SMUG1, and GADD45A participate in DNA demeth- products [1, 7, 44–49]. Te Hsp90 inhibitor 17-DMAG ylation through DNA hydroxymethylation, deamination, diminishes the binding of DNMT1 and of the histone base excision repair (BER), and other mechanisms [4, 13– methyltransferase EZH2 to Hsp90, attenuates the inter- 19]. For example, a molecular complex containing AID, action between DNMT1 and EZH2, and mediates the TDG, and GADD45A participates in DNA demethyla- depletion of DNMT1 and EZH2 [50]. HDAC inhibitors tion via the BER pathway [20]. (HDACi) afect DNA methylation through a variety of Many factors participate in molecular complexes that mechanisms. Vorinostat downregulates transcription of afect DNA methylation or demethylation, participate DNMT1 and DNMT3B and changes DNA methylation of in methylation-dependent targeting of other molecular TERT and DLC1 [51–53]. Panobinostat depletes protein factors to genome regions, or regulate binding and/or levels of DNMT1 and EZH2 and disrupts DNMT1 inter- activities of DNMTs, TETs, and other epigenetic factors, action with EZH2 and the polycomb repressive complex either directly or via intermediate metabolites. Exam- 2 (PRC2) [50]. Trichostatin A downregulates gene and ples include MBD1, MBD2, MBD3, MBD4, PCNA, USP7 protein expression of DNMT1 and induces global DNA (HAUSP), DNMT3L, UHRF1, UHRF2, DMAP1, ZBTB4, hypomethylation [54]. Belinostat reduces global DNA ZBTB33 (KAISO), ZBTB38, RBPJ, G9A (EHMT2), KAT5 methylation and depletes protein levels of the PRC2 sub- (TIP60), SUV39H1, HDAC1, SIRT1, EZH2, CSNK1D, units EZH2 and SUZ12 [55]. CSNK1E, and SUMO1 (Additional fle 1: Table S1) [4, 13, Among examples of the infuence of DNA meth- 21–29]. IDH1 and IDH2 mutations lead to overproduc- ylation on tumor sensitivity to treatment, MGMT pro- tion of cellular metabolites which interfere with TET- moter methylation downregulates MGMT expression, mediated conversion of 5-methylcytosine (5-mC) to disrupting MGMT role in DNA repair, which is linked 5-hydroxymethylcytosine (5-hmC) [30]. GLP (EHMT1), to resistance to nitrosourea-based antitumor agents, G9A (EHMT2), ZFP57, DPPA3 (PGC7, or STELLA), temozolomide, and radiation [37, 56, 57]. Specifc DNA Vural et al. Clin Epigenet (2021) 13:49 Page 3 of 23 methylation patterns or methylation of individual genes Drug response data have been associated with resistance to diferent types To examine the relationship between pretreatment GMD of cancer drugs, e.g., the platinum compound cisplatin, expression and tumor response to antitumor agents, poly(ADP-ribose) polymerase
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