10.6084/m9.figshare.7724987.v1 Ashok Sharma Ashok Sharma Mustafa Albahrani Mustafa Albahrani Wa Zhang Wa Zhang Christina N. Kufel Christina N. Kufel Smitha R. James Smitha R. James Kunle Odunsi Kunle Odunsi David Klinkebiel David Klinkebiel Adam R. Karpf Adam R. Karpf Epigenetic activation of <i>POTE</i> genes in ovarian cancer Taylor & Francis Group 2019 POTE Ovarian cancer high-grade serous ovarian cancer DNA hypomethylation pericentromeres LINE1 2019-02-15 05:56:57 Dataset https://tandf.figshare.com/articles/dataset/Epigenetic_activation_of_i_POTE_i_genes_in_ovarian_cancer/7724987 <p>The <i>POTE</i> gene family consists of 14 homologous genes localized to autosomal pericentromeres, and a sub-set of <i>POTEs</i> are cancer-testis antigen (CTA) genes. <i>POTE</i>s are over-expressed in epithelial ovarian cancer (EOC), including the high-grade serous subtype (HGSC), and expression of individual <i>POTEs</i> correlates with chemoresistance and reduced survival in HGSC. The mechanisms driving <i>POTE</i> overexpression in EOC and other cancers is unknown. Here, we investigated the role of epigenetics in regulating <i>POTE</i> expression, with a focus on DNA hypomethylation. Consistent with their pericentromeric localization, <i>Pan-POTE</i> expression in EOC correlated with expression of the pericentromeric repeat <i>NBL2</i>, which was not the case for non-pericentromeric CTAs. <i>POTE</i> genomic regions contain <i>LINE-1</i> (L1) sequences, and <i>Pan-POTE</i> expression correlated with both global and <i>POTE</i>-specific L1 hypomethylation in EOC. Analysis of individual <i>POTEs</i> using RNA-seq and DNA methylome data from fallopian tube epithelia (FTE) and HGSC revealed that <i>POTEs C, E, and F</i> have increased expression in HGSC in conjunction with DNA hypomethylation at 5’ promoter or enhancer regions. Moreover, <i>POTEs C/E/F</i> showed additional increased expression in recurrent HGSC in conjunction with 5’ hypomethylation, using patient-matched samples. Experiments using decitabine treatment and DNMT knockout cell lines verified a functional contribution of DNA methylation to <i>POTE</i> repression, and epigenetic drug combinations targeting histone deacetylases (HDACs) and histone methyltransferases (HMTs) in combination with decitabine further increased <i>POTE</i> expression. In summary, several alterations of the cancer epigenome, including pericentromeric activation, global and locus-specific <i>L1</i> hypomethylation, and locus-specific 5’ CpG hypomethylation, converge to promote <i>POTE</i> expression in ovarian cancer.</p>