Epigenetic activation of POTE genes in ovarian cancer
The POTE gene family consists of 14 homologous genes localized to autosomal pericentromeres, and a sub-set 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 c...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2019-02-01
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| Series: | Epigenetics |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/15592294.2019.1581590 |
| _version_ | 1797678902518218752 |
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| author | Ashok Sharma Mustafa Albahrani Wa Zhang Christina N. Kufel Smitha R. James Kunle Odunsi David Klinkebiel Adam R. Karpf |
| author_facet | Ashok Sharma Mustafa Albahrani Wa Zhang Christina N. Kufel Smitha R. James Kunle Odunsi David Klinkebiel Adam R. Karpf |
| author_sort | Ashok Sharma |
| collection | DOAJ |
| description | The POTE gene family consists of 14 homologous genes localized to autosomal pericentromeres, and a sub-set 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. |
| first_indexed | 2024-03-11T23:06:41Z |
| format | Article |
| id | doaj.art-9c46d85718e44899b4bbd759d5cb7d44 |
| institution | Directory Open Access Journal |
| issn | 1559-2294 1559-2308 |
| language | English |
| last_indexed | 2024-03-11T23:06:41Z |
| publishDate | 2019-02-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Epigenetics |
| spelling | doaj.art-9c46d85718e44899b4bbd759d5cb7d442023-09-21T13:09:21ZengTaylor & Francis GroupEpigenetics1559-22941559-23082019-02-0114218519710.1080/15592294.2019.15815901581590Epigenetic activation of POTE genes in ovarian cancerAshok Sharma0Mustafa Albahrani1Wa Zhang2Christina N. Kufel3Smitha R. James4Kunle Odunsi5David Klinkebiel6Adam R. Karpf7University of Nebraska Medical CenterUniversity of Nebraska Medical CenterUniversity of Nebraska Medical CenterRoswell Park Comprehensive Cancer CenterRoswell Park Comprehensive Cancer CenterRoswell Park Comprehensive Cancer CenterUniversity of Nebraska Medical CenterUniversity of Nebraska Medical CenterThe POTE gene family consists of 14 homologous genes localized to autosomal pericentromeres, and a sub-set 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.http://dx.doi.org/10.1080/15592294.2019.1581590poteovarian cancerhigh-grade serous ovarian cancerdna hypomethylationpericentromeresline1 |
| spellingShingle | Ashok Sharma Mustafa Albahrani Wa Zhang Christina N. Kufel Smitha R. James Kunle Odunsi David Klinkebiel Adam R. Karpf Epigenetic activation of POTE genes in ovarian cancer Epigenetics pote ovarian cancer high-grade serous ovarian cancer dna hypomethylation pericentromeres line1 |
| title | Epigenetic activation of POTE genes in ovarian cancer |
| title_full | Epigenetic activation of POTE genes in ovarian cancer |
| title_fullStr | Epigenetic activation of POTE genes in ovarian cancer |
| title_full_unstemmed | Epigenetic activation of POTE genes in ovarian cancer |
| title_short | Epigenetic activation of POTE genes in ovarian cancer |
| title_sort | epigenetic activation of pote genes in ovarian cancer |
| topic | pote ovarian cancer high-grade serous ovarian cancer dna hypomethylation pericentromeres line1 |
| url | http://dx.doi.org/10.1080/15592294.2019.1581590 |
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