Sharma, Ashok Albahrani, Mustafa Zhang, Wa Kufel, Christina N. James, Smitha R. Odunsi, Kunle Klinkebiel, David R. Karpf, Adam Epigenetic activation of <i>POTE</i> genes in ovarian cancer <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> POTE;Ovarian cancer;high-grade serous ovarian cancer;DNA hypomethylation;pericentromeres;LINE1 2019-02-15
    https://tandf.figshare.com/articles/dataset/Epigenetic_activation_of_i_POTE_i_genes_in_ovarian_cancer/7724987
10.6084/m9.figshare.7724987.v1