KRAS4B oncogenic mutants promote non-small cell lung cancer progression via the interaction of deubiquitinase USP25 with RNF31

Abstract

Kirsten rat sarcoma viral oncogene homolog (KRAS) oncogenic mutations are genetic drivers in various cancers, including non-small cell lung cancer (NSCLC). However, the regulatory mechanisms underlying the progression of NSCLC driven by oncogenic KRAS mutants are incompletely understood. Here, we show that ubiquitin specific peptidase 25 (USP25) impedes ring finger protein 31 (RNF31)-mediated linear ubiquitination of KRAS oncogenic mutants (KRAS^muts) independently of its deubiquitinase activity, which facilitates the plasma membrane (PM) localization and the downstream oncogenic signaling of KRAS^muts. Importantly, knockout (KO) of USP25 effectively suppresses tumor growth and RAS signaling in KRAS^muts-driven autochthonous NSCLC mouse models and xenograft models, which is restored by additional deletion or inhibition of RNF31. Notably, knockin of USP25^C178A in KRas^G12D-driven NSCLC models fails to inhibit cancer progression and reconstitution of USP25^C178A into USP25 KO A549 cells restores tumor growth. These findings identify previously uncharacterized roles of USP25 and RNF31 in oncogenic KRAS-driven NSCLC progression and provide potential therapeutic targets for KRAS^muts-related cancers.