Epigenetic activation of POTE genes in ovarian cancer

Abstract

The POTE gene family consists of 14 homologous genes localized to autosomal pericentromeres, and a subset of POTEs are cancer-testis antigen (CTA) genes. POTEs are over-expressed in epithelial ovarian cancer (EOC), including the high-grade serous subtype (HGSC), and expression of individual POTEs correlates with chemoresistance and reduced survival in HGSC. The mechanisms driving POTE overexpression in EOC and other cancers is unknown. Here, we investigated the role of epigenetics in regulating POTE expression, with a focus on DNA hypomethylation. Consistent with their pericentromeric localization, Pan-POTE expression in EOC correlated with expression of the pericentromeric repeat NBL2, which was not the case for non-pericentromeric CTAs. POTE genomic regions contain LINE-1 (L1) sequences, and Pan-POTE expression correlated with both global and POTE-specific L1 hypomethylation in EOC. Analysis of individual POTEs using RNA-seq and DNA methylome data from fallopian tube epithelia (FTE) and HGSC revealed that POTEs C, E, and F have increased expression in HGSC in conjunction with DNA hypomethylation at 5' promoter or enhancer regions. Moreover, POTEs C/E/F 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 POTE repression, and epigenetic drug combinations targeting histone deacetylases (HDACs) and histone methyltransferases (HMTs) in combination with decitabine further increased POTE expression. In summary, several alterations of the cancer epigenome, including pericentromeric activation, global and locus-specific L1 hypomethylation, and locus-specific 5' CpG hypomethylation, converge to promote POTE expression in ovarian cancer.

Epigenetic Biomarkers in the Management of Ovarian Cancer: Current Prospectives

“…In addition expression of individual gene in POTE gene family correlated with chemoresistance and poor clinical outcome in HGSOC patients. Furthermore, several epigenetic alternations (pericentromeric activation, global and locus-specific L1 hypomethylation, and locus-specific 5' CpG hypomethylation) served as a determinant for regulation of epigenetic activation of POTE gene (Sharma et al, 2019).…”

Global DNA Hypomethylation in Epithelial Ovarian Cancer: Passive Demethylation and Association with Genomic Instability

“…In agreement, DNA hypomethylation occurs at repetitive elements (RE), including the interspersed retrotransposon LINE-1 [7], which accounts for~17% of the genome. Global DNA hypomethylation (GDHO) is also associated with hypomethylation and activation of cancer-testis or cancer-germline (CG) genes [8][9][10][11][12][13]. Epigenomic approaches have revealed that GDHO is not random or driven solely by changes at RE, but rather is localized to large genomic regions referred to as hypomethylated blocks [14][15][16].…”

Epithelial Ovarian Cancer and the Immune System: Biology, Interactions, Challenges and Potential Advances for Immunotherapy

“…CTAs are normally involved in self-renewal and differentiation of pluripotent and multipotent stem cells, while aberrant expression is associated with cancer transformation and abnormal differentiation of cancer stem cells [ 138 ]. Studies have implicated global and locus-specific DNA hypomethylation as a key mechanism promoting CTA expression in cancer, including epithelial ovarian cancer [ 139 ]. Cancer patients often develop spontaneous immune reactions against CTAs demonstrating their immunogenicity [ 137 ].…”