Functions And Mechanism Of TRPS1 Regulating HDAC2 In Breast Cancer

Breast cancer is the second leading cause of cancer-related deaths in women worldwide.The incidence of breast cancer is increasing year by year.TRPS1 transcription factor is the only known atypical member of GATA transcriptional factor family.Deletion or mutation of TRPS1 gene may cause tricho-rhino-phalangeal syndrome.However,the potential role and molecular mechanism of TRPS1 in cancer progression is largely unknown.In current study,our molecular and biochemical studies demonstrated that TRPS1 positively regulates HDAC2 via stabilizing HDAC2 in ubiquitin-dependent way.Mechanically,TRPS1 scaffolding functions to recruit USP4 and HDAC2 to enhance interaction between USP4 and HDAC2,leading to HDAC2 deubiquitination and H4K16 deacetylation.TRPS1 controls the transcription repressive function of HDAC2.Detailed genome-wide and molecular studies reveal TRPS1-USP4-HDAC2 axis represses a set of cell growth-related genes,including AES,CASP7,and PERP,indicating the important role of TRPS1-USP4-HDAC2 axis in tumor growth.In vitro and in vivo experiments confirmed silencing TRPS1 reduced tumor growth and additional overexpression HDAC2 restored tumor growth.Taken together,our study deciphers TRPS1-USP4-HDAC2 axis as a novel mechanism,by which TRPS1,USP4 and HDAC2 contribute to tumor growth,and reveals the scaffolding function of TPRS1 in USP4-directed HDAC2 deubiquitination to provide new mechanistic insights into how TRPS1,ubiquitin system,and histone modification system crosstalk to confer tumor growth.