Epigenetic activation of POTE genes in ovarian cancer.

Carcinoma, Ovarian Epithelial / genetics Cell Line, Tumor DNA Methylation Epigenesis, Genetic Female Gene Expression Regulation, Neoplastic Humans Long Interspersed Nucleotide Elements Ovarian Neoplasms / genetics Promoter Regions, Genetic Proteins / genetics Up-Regulation
DNA hypomethylation LINE1 Ovarian cancer POTE high-grade serous ovarian cancer pericentromeres

Journal

Epigenetics
ISSN: 1559-2308
Titre abrégé: Epigenetics
Pays: United States
ID NLM: 101265293

Informations de publication

Date de publication:
02 2019
Historique:
pubmed: 16 2 2019
medline: 15 5 2020
entrez: 16 2 2019
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1080/15592294.2019.1581590 PMID: 30764732 PMC: PMC6557602
pubmed: 30764732
doi: 10.1080/15592294.2019.1581590
pmc: PMC6557602
doi:

Substances chimiques

Proteins 0

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

185-197

Subventions

Organisme : NCI NIH HHS
ID : P30 CA016056
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA036727
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA116674
Pays : United States

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Auteurs

Ashok Sharma (A)

a Eppley Institute , University of Nebraska Medical Center , Omaha , NE , USA.
b Fred & Pamela Buffett Cancer Center , University of Nebraska Medical Center , Omaha , NE , USA.

Mustafa Albahrani (M)

a Eppley Institute , University of Nebraska Medical Center , Omaha , NE , USA.
b Fred & Pamela Buffett Cancer Center , University of Nebraska Medical Center , Omaha , NE , USA.

Wa Zhang (W)

a Eppley Institute , University of Nebraska Medical Center , Omaha , NE , USA.
b Fred & Pamela Buffett Cancer Center , University of Nebraska Medical Center , Omaha , NE , USA.

Christina N Kufel (CN)

c Department of Pharmacology and Therapeutics , Roswell Park Comprehensive Cancer Center , Buffalo , NY , USA.

Smitha R James (SR)

c Department of Pharmacology and Therapeutics , Roswell Park Comprehensive Cancer Center , Buffalo , NY , USA.

Kunle Odunsi (K)

d Department of Immunology , Roswell Park Comprehensive Cancer Center , Buffalo , NY , USA.
e Department of Gynecologic Oncology , Roswell Park Comprehensive Cancer Center , Buffalo , NY , USA.
f Center for Immunotherapy , Roswell Park Comprehensive Cancer Center , Buffalo , NY , USA.

David Klinkebiel (D)

b Fred & Pamela Buffett Cancer Center , University of Nebraska Medical Center , Omaha , NE , USA.
g Department of Biochemistry and Molecular Biology , University of Nebraska Medical Center , Omaha , NE , USA.

Adam R Karpf (AR)

a Eppley Institute , University of Nebraska Medical Center , Omaha , NE , USA.
b Fred & Pamela Buffett Cancer Center , University of Nebraska Medical Center , Omaha , NE , USA.
c Department of Pharmacology and Therapeutics , Roswell Park Comprehensive Cancer Center , Buffalo , NY , USA.

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Classifications MeSH

questionsmedicales.fr › Maladies endocriniennes › Troubles gonadiques › Maladies ovariennes › Tumeurs de l'ovaire › Carcinome épithélial de l'ovaire › Epigenetic activation of POTE genes in ovarian cancer.
questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › Epigenetic activation of POTE genes in ovarian cancer.
questionsmedicales.fr › Phénomènes génétiques › Méthylation de l'ADN › Epigenetic activation of POTE genes in ovarian cancer.
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Épigenèse génétique › Epigenetic activation of POTE genes in ovarian cancer.
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Régulation de l'expression des gènes tumoraux › Epigenetic activation of POTE genes in ovarian cancer.
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Epigenetic activation of POTE genes in ovarian cancer.
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Composants de génome › Séquences répétées dispersées › Rétroéléments › Éléments LINE › Epigenetic activation of POTE genes in ovarian cancer.
questionsmedicales.fr › Maladies endocriniennes › Troubles gonadiques › Maladies ovariennes › Tumeurs de l'ovaire › Epigenetic activation of POTE genes in ovarian cancer.
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Composants de génome › Gènes › Composants de gène › Éléments de régulation transcriptionnelle › Régions promotrices (génétique) › Epigenetic activation of POTE genes in ovarian cancer.
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Epigenetic activation of POTE genes in ovarian cancer.
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes pharmacologiques › Régulation positive › Epigenetic activation of POTE genes in ovarian cancer.