HIFI-α activation underlies a functional switch in the paradoxical role of Ezh2/PRC2 in breast cancer.
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.
Cancer 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;
Sylvia
S
Mahara
Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Agency for Science, Technology and Research, Biopolis, Singapore 138672;
Puay Leng
PL
Lee
Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Agency for Science, Technology and Research, Biopolis, Singapore 138672;
Min
M
Feng
Institute 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;
Vinay
V
Tergaonkar
Cancer 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.
Wee Joo
WJ
Chng
Cancer 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.
Qiang
Q
Yu
D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2
EZH2; FOXM1; PRC2; breast cancer; hypoxia