The deubiquitinase USP28 stabilizes LSD1 and confers stem-cell-like traits to breast cancer cells.
LSD1 is a critical chromatin modulator that controls cellular pluripotency and differentiation through the demethylation of H3K4me1/2. Overexpression of LSD1 has been observed in many types of tumors and is correlated with its oncogenic effects in tumorigenesis. However, the mechanism leading to LSD1 upregulation in tumors remains unclear. Using an unbiased siRNA screening against all the human deubiquitinases, we identified USP28 as a bona fide deubiquitinase of LSD1. USP28 interacted with and stabilized LSD1 via deubiquitination. USP28 overexpression correlated with LSD1 upregulation in multiple cancer cell lines and breast tumor samples. Knockdown of USP28 resulted in LSD1 destabilization, leading to the suppression of cancer stem cell (CSC)-like characteristics in vitro and inhibition of tumorigenicity in vivo, which can be rescued by ectopic LSD1 expression. Our study reveals a critical mechanism underlying the epigenetic regulation by USP28 and provides another treatment approach against breast cancer.
Department of Molecular and Biomedical Pharmacology, University of Kentucky, College of Medicine, Lexington, KY 40506, USA; Markey Cancer Center, University of Kentucky, College of Medicine, Lexington, KY 40506, USA. Electronic address: yadi.wu@uky.edu.
Yadi
Y
Wu
Yifan
Y
Wang
Xiuwei H
XH
Yang
Tiebang
T
Kang
Yongxiang
Y
Zhao
Chi
C
Wang
B Mark
BM
Evers
Binhua P
BP
Zhou
D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002454:Cell Differentiation / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D005260:Female; D057809:HEK293 Cells; D056466:Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D014411:Neoplastic Stem Cells / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D034741:RNA, Small Interfering / Q000235:genetics; D014162:Transfection; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism*
D034741:RNA, Small Interfering; C442902:USP28 protein, human; D056466:Histone Demethylases; C495195:KDM1A protein, human; D043222:Ubiquitin Thiolesterase