Systematic characterization of mutations altering protein degradation in human cancers.

The ubiquitin-proteasome system (UPS) is the primary route for selective protein degradation in human cells. The UPS is an attractive target for novel cancer therapies, but the precise UPS genes and substrates important for cancer growth are incompletely understood. Leveraging multi-omics data across more than 9,000 human tumors and 33 cancer types, we found that over 19% of all cancer driver genes affect UPS function. We implicate transcription factors as important substrates and show that c-Myc stability is modulated by CUL3. Moreover, we developed a deep learning model (deepDegron) to identify mutations that result in degron loss and experimentally validated the prediction that gain-of-function truncating mutations in GATA3 and PPM1D result in increased protein stability. Last, we identified UPS driver genes associated with prognosis and the tumor microenvironment. This study demonstrates the important role of UPS dysregulation in human cancer and underscores the potential therapeutic utility of targeting the UPS.
Competing Interests: Declaration of interests S.J.E. is a member of the Molecular Cell advisory board. X.S.L. is a cofounder, board member, SAB, and consultant of GV20 Oncotherapy and its subsidiaries and the SAB of 3DMedCare; a consultant for Genentech; a stockholder of BMY, TMO, WBA, ABT, ABBV, and JNJ; and receives research funding from Takeda and Sanofi. M.B. is a consultant to and receives sponsored research support from Novartis. M.B. serves on the SAB of H3 Biomedicine, Kronos Bio, and GV20 Oncotherapy.
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