USP10-mediated deubiquitination and activation of KRAS mutants promotes colorectal cancer via a novel USP10/KRAS positive feedback circuit

Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation is associated with the poor prognosis of colorectal cancer (CRC) patients, but the therapeutic strategies targeting KRAS are limited, and novel intervention strategies are urgently needed. The dysfunction of deubiquitinases (DUBs) is widely involved in the progression of malignancy, and DUBs are considered ideal anti-tumor targets due to their well-defined structures and catalytic sites. In our study, through DUB inhibitors screening and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis, we identified that ubiquitin-specific protease 10 (USP10) functions as a potent DUB regulating <i>KRAS</i> mutants' activity. Mechanistically, USP10 directly binds to and promotes <i>KRAS</i> variants' activity across different mutants by removing the latter's non-proteolytic ubiquitination chains mainly containing K6, K11, K27 and K29-linkage; while the activated <i>KRAS</i> mutants reciprocally upregulate USP10 levels by phosphorylating the latter at Thr42/Ser337, therefore forming a positive feedback circuit and synergistically promoting <i>KRAS</i>-mutant CRC growth. Moreover, we found that USP10 is elevated in <i>KRAS</i>-mutant CRC tissues and depletion of USP10 preferentially impeded <i>KRAS</i>-mutant CRC growth <i>in vitro</i>/<i>in vivo</i>. Our findings not only uncover the critical roles of the USP10/KRAS positive feedback circuit in promoting <i>KRAS</i>-mutant CRC growth, but also offer novel therapeutic strategies for CRC patients harboring KRAS variants across different mutants by targeting USP10.