Aspirin suppresses cytoprotective autophagy and colorectal tumorigenesis through HSP90AA1 K410 acetylation-mediated ULK1 ubiquitination and degradation

Abstract Colorectal cancer (CRC) remains a significant global health challenge with high recurrence rates despite therapeutic advancements, underscoring the urgency for innovative therapeutic strategies. Clinical trials have demonstrated that aspirin treatment correlates with reduced cancer incidence, recurrence, metastasis, and mortality, yet the precise intricacies of aspirin’s role in tumorigenesis and its underlying mechanisms remain incompletely understood. This study unveils the inhibitory impact of aspirin on CRC by suppressing cell cytoprotective autophagy. Mechanistically, aspirin increases the acetylation level of HSP90AA1, disrupting its tumor-promoting and cytoprotective autophagy-stimulating functions. Genetic deletion of HSP90AA1 compromises aspirin’s inhibitory effects on CRC cells. Specifically, lysine 410 (K410) is identified as the specific site on HSP90AA1 acetylated by aspirin. HSP90AA1 with the K410Q acetylation mimetic loses its abilities to promote tumorigenesis and cytoprotective autophagy. Furthermore, aspirin treatment induces enhanced ubiquitination and degradation of ULK1, a key regulator of autophagy initiation, attributed to the reduced interaction between HSP90AA1 and ULK1 resulting from K410 acetylation of HSP90AA1 triggered by aspirin. Our findings elucidate the role of aspirin in inhibiting cytoprotective autophagy in CRC and provide novel mechanistic insights into its tumor-suppressing capabilities, suggesting a promising therapeutic approach against CRC involving aspirin and the targeting of HSP90AA1 acetylation.