USP25 maintains KRAS expression and inhibiting the deubiquitinase suppresses KRAS signaling in human cancer

作者：Huailu Ma, Huiyuan Guan, Xiao Sun, Lingzhi Wu, Mengjiao Cai, Xinghua Zhen, Xiang Shen, Suxia Han, Guang‐Xue Liu, Jin Peng, Pumin Zhang · 发表于：Journal of Biological Chemistry · 年份：2025 · DOI：10.1016/j.jbc.2025.110337 · 被引用次数：3 · 研究领域：Ubiquitin and proteasome pathways、Cell death mechanisms and regulation、Glycosylation and Glycoproteins Research

KRAS is a prominent oncogene mutated in a large number of human malignancies, particularly in pancreatic, colorectal, and lung tumors. We demonstrate here that KRAS, including its various activating mutants, is subjected to ubiquitin-mediated proteasomal degradation in cancer cells. Through an siRNA-based screening of deubiquitinases, we identified USP25 as a deubiquitinase for KRAS. Depleting USP25 expression increases ubiquitination and proteasomal degradation of KRAS, leading to the suppression of its oncogenic activity. We further show that USP25 inhibitors we have discovered are capable of destabilizing KRAS in cancer cells and are efficacious in blocking tumor xenograft growth in mice. These findings provide evidence supporting the notion that targeting the deubiquitinase USP25 can effectively, albeit indirectly, suppress KRAS and potentially aid in the treatment of tumors driven by KRAS-activating mutations.