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.