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As a member of the 11-gene “death-from-cancer” gene expression signature, overexpression of the  Ubiquitin-Specific Protease 22  ( USP22 ) was associated with poor prognosis in various human malignancies. To investigate the function of USP22 in cancer development and progression, we sought to detect common USP22-dependent molecular mechanisms in human colorectal and breast cancer cell lines. We performed mRNA-seq to compare gene expression profiles of various colorectal (SW837, SW480, HCT116) and mammary (HCC1954 and MCF10A) cell lines upon siRNA-mediated knockdown of USP22. Intriguingly, while USP22 depletion had highly heterogeneous effects across the cell lines, all cell lines displayed a common reduction in the expression of  Heat Shock Protein 90 Alpha Family Class B Member 1  ( HSP90AB1 ). The downregulation of HSP90AB1 was confirmed at the protein level in these cell lines as well as in colorectal and mammary tumors in mice with tissue-specific  Usp22  deletions. Mechanistically, we detected a significant reduction of H3K9ac on the  HSP90AB1  gene in USP22-deficient cells. Interestingly, USP22-deficient cells displayed a high dependence on  HSP90AB1  expression and diminishing HSP90 activity further using the HSP90 inhibitor Ganetespib resulted in increased therapeutic vulnerability in both colorectal and breast cancer cells in vitro. Accordingly, subcutaneously transplanted CRC cells deficient in  USP22  expression displayed increased sensitivity towards Ganetespib treatment in vivo. Together, we discovered that  HSP90AB1  is USP22-dependent and that cooperative targeting of USP22 and HSP90 may provide an effective approach to the treatment of colorectal and breast cancer.

USP22-dependent HSP90AB1 expression promotes resistance to HSP90 inhibition in mammary and colorectal cancer