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HIFI-α Activation Underlies a Functional Switch in the Paradoxical Role of Ezh2/PRC2 in Breast Cancer. (PNAS, June 2016)

Mahara S1, Lee PL2, Feng M2, Tergaonkar V3, Chng WJ4, Yu Q5

1Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Agency for Science, Technology and Research, Biopolis, Singapore 138672; Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599;
2Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Agency for Science, Technology and Research, Biopolis, Singapore 138672;
3Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Biopolis, Singapore 138672; Centre for Cancer Biology, University of South Australia, Adelaide, SA 5000, Australia; SA Pathology, Adelaide, SA 5000, Australia;
4Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599; Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597; Department of Haematology-Oncology, National University Cancer Institute of Singapore, National University Health System, Singapore 119047; mdccwj@nus.edu.sg yuq@gis.a-star.edu.sg.
5Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Agency for Science, Technology and Research, Biopolis, Singapore 138672; Cancer Research Institute, Jinan University, Guangzhou 510632, China; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597; Cancer and Stem Cell Biology, Duke-National University of Singapore Graduate Medical School Singapore, Singapore 169857 mdccwj@nus.edu.sg yuq@gis.a-star.edu.sg

Abstract:

Despite the established oncogenic function of Polycomb repressive complex 2 (PRC2) in human cancers, its role as a tumor suppressor is also evident; however, the mechanism underlying the regulation of the paradoxical functions of PRC2 in tumorigenesis is poorly understood. Here we show that hypoxia-inducible factor 1, α-subunit (HIFI-α) is a crucial modulator of PRC2 and enhancer of zeste 2 (EZH2) function in breast cancer. Interrogating the genomic expression of breast cancer indicates high HIF1A activity correlated with high EZH2 expression but low PRC2 activity in triple-negative breast cancer compared with other cancer subtypes. In the absence of HIFIA activation, PRC2 represses the expression of matrix metalloproteinase genes (MMPs) and invasion, whereas a discrete Ezh2 complexed with Forkhead box M1 (FoxM1) acts to promote the expression of MMPs. HIF1-α induction upon hypoxia results in PRC2 inactivation by selective suppression of the expression of suppressor of zeste 12 protein homolog (SUZ12) and embryonic ectoderm development (EED), leading to a functional switch toward Ezh2/FoxM1-dependent induction of the expression of MMPs and invasion. Our study suggests a tumor-suppressive function of PRC2, which is restricted by HIF1-α, and an oncogenic function of Ezh2, which cooperates with FoxM1 to promote invasion in triple-negative breast cancer.

KEYWORDS: EZH2; FOXM1; PRC2; breast cancer; hypoxia

 

PMID: 27303043