TRIM24-mediated K27-linked ubiquitination of ULK1 alleviates energy stress-induced autophagy and promote prostate cancer growth in the context of SPOP mutation.

Abstract

SPOP, the most frequently mutated gene in prostate cancer, has been implicated in the aberrant activation of stress granules, presenting significant challenges in disease management. However, the mechanistic link between SPOP mutations and cellular energy stress remains inadequately explored. In this study, we demonstrate that ULK1 expression is positively correlated with both loss-of-function mutations in SPOP and the upregulation of the E3 ubiquitin ligase TRIM24 in human prostate cancer specimens. Mechanistically, SPOP mutations induce the upregulation of TRIM24, which subsequently binds to ULK1 and catalyzes its non-degradative K27-linked polyubiquitylation. This post-translational modification enhances the stability of ULK1, facilitating cellular adaptation to energy stress and consequently promoting prostate cancer progression. Notably, pharmacological inhibition of TRIM24 using TRIM24-PROTAC (proteolysis-targeting chimera) effectively suppressed tumor growth in mice bearing SPOP-mutant prostate cancer cells. Collectively, these findings elucidate a pivotal role of SPOP mutations in modulating energy stress responses via TRIM24-mediated ULK1 ubiquitylation and underscore the therapeutic potential of targeting TRIM24 in SPOP-mutant prostate cancers.