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Epigenetic derepression converts PPARγ into a druggable target in triple-negative and endocrine-resistant breast cancers

Authors :
Ser Yue Loo
Nicholas L. Syn
Angele Pei-Fern Koh
Janet Cheng-Fei Teng
Amudha Deivasigamani
Tuan Zea Tan
Aye Aye Thike
Shireen Vali
Shweta Kapoor
Xiaoyuan Wang
Jiong Wei Wang
Puay Hoon Tan
George W. Yip
Gautam Sethi
Ruby Yun-Ju Huang
Kam Man Hui
Lingzhi Wang
Boon Cher Goh
Alan Prem Kumar
Source :
Cell Death Discovery, Vol 7, Iss 1, Pp 1-15 (2021)
Publication Year :
2021
Publisher :
Nature Publishing Group, 2021.

Abstract

Abstract Clinical trials repurposing peroxisome proliferator-activated receptor-gamma (PPARγ) agonists as anticancer agents have exhibited lackluster efficacy across a variety of tumor types. Here, we report that increased PPARG expression is associated with a better prognosis but is anticorrelated with histone deacetylase (HDAC) 1 and 2 expressions. We show that HDAC overexpression blunts anti-proliferative and anti-angiogenic responses to PPARγ agonists via transcriptional and post-translational mechanisms, however, these can be neutralized with clinically approved and experimental HDAC inhibitors. Supporting this notion, concomitant treatment with HDAC inhibitors was required to license the tumor-suppressive effects of PPARγ agonists in triple-negative and endocrine-refractory breast cancer cells, and combination therapy also restrained angiogenesis in a tube formation assay. This combination was also synergistic in estrogen receptor-alpha (ERα)–positive cells because HDAC blockade abrogated ERα interference with PPARγ-regulated transcription. Following a pharmacokinetics optimization study, the combination of rosiglitazone and a potent pan-HDAC inhibitor, LBH589, stalled disease progression in a mouse model of triple-negative breast cancer greater than either of the monotherapies, while exhibiting a favorable safety profile. Our findings account for historical observations of de-novo resistance to PPARγ agonist monotherapy and propound a therapeutically cogent intervention against two aggressive breast cancer subtypes.

Details

Language :
English
ISSN :
20587716
Volume :
7
Issue :
1
Database :
Directory of Open Access Journals
Journal :
Cell Death Discovery
Publication Type :
Academic Journal
Accession number :
edsdoj.82fb2ea92fce4d45b46ee3f019c45a37
Document Type :
article
Full Text :
https://doi.org/10.1038/s41420-021-00635-5