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Targeting IDH1 as a Prosenescent Therapy in High-grade Serous Ovarian Cancer
Journal article   Open access   Peer reviewed

Targeting IDH1 as a Prosenescent Therapy in High-grade Serous Ovarian Cancer

Erika S Dahl, Raquel Buj, Kelly E Leon, Jordan M Newell, Yuka Imamura, Benjamin G Bitler, Nathaniel W Snyder and Katherine M Aird
Molecular cancer research, v 17(8), pp 1710-1720
Aug 2019
DOI: https://doi.org/10.1158/1541-7786.MCR-18-1233
PMID: 31110157
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://doi.org/10.1158/1541-7786.mcr-18-1233View
Accepted (AM)Open Access (License Unspecified),  Open

Abstract

Apoptosis Carcinoma, Ovarian Epithelial - genetics Carcinoma, Ovarian Epithelial - metabolism Carcinoma, Ovarian Epithelial - pathology Cell Proliferation Cellular Senescence Cystadenocarcinoma, Serous - genetics Cystadenocarcinoma, Serous - metabolism Cystadenocarcinoma, Serous - pathology E2F Transcription Factors - genetics E2F Transcription Factors - metabolism Epigenesis, Genetic Female Gene Expression Regulation, Neoplastic Histones - genetics Histones - metabolism Humans Isocitrate Dehydrogenase - genetics Isocitrate Dehydrogenase - metabolism Neoplasm Grading Survival Rate Tumor Cells, Cultured
Epithelial ovarian cancer (EOC) is the deadliest gynecologic cancer. High-grade serous carcinoma (HGSC) is the most frequently diagnosed and lethal histosubtype of EOC. A significant proportion of patients with HGSC relapse with chemoresistant disease. Therefore, there is an urgent need for novel therapeutic strategies for HGSC. Metabolic reprogramming is a hallmark of cancer cells, and targeting metabolism for cancer therapy may be beneficial. Here, we found that in comparison with normal fallopian tube epithelial cells, HGSC cells preferentially utilize glucose in the TCA cycle and not for aerobic glycolysis. This correlated with universally increased TCA cycle enzyme expression in HGSC cells under adherent conditions. HGSC disseminates as tumor cell spheroids within the peritoneal cavity. We found that wild-type isocitrate dehydrogenase I ( ) is the only TCA cycle enzyme upregulated in both adherent and spheroid conditions and is associated with reduced progression-free survival. IDH1 protein expression is also increased in patients with primary HGSC tumors. Pharmacologic inhibition or knockdown of IDH1 decreased proliferation of multiple HGSC cell lines by inducing senescence. Mechanistically, suppression of IDH1 increased the repressive histone mark H3K9me2 at multiple E2F target gene loci, which led to decreased expression of these genes. Altogether, these data suggest that increased IDH1 activity is an important metabolic adaptation in HGSC and that targeting wild-type IDH1 in HGSC alters the repressive histone epigenetic landscape to induce senescence. IMPLICATIONS: Inhibition of IDH1 may act as a novel therapeutic approach to alter both the metabolism and epigenetics of HGSC as a prosenescent therapy.

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32 citations in Web of Science
28 citations in Scopus

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UN Sustainable Development Goals (SDGs)

This publication has contributed to the advancement of the following goals:

#3 Good Health and Well-Being

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Collaboration types
Domestic collaboration
Web of Science research areas
Cell Biology
Oncology
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