Acetylation of GPRC5A at Lys348 facilitates cisplatin resistance and promotes the recurrence and poor prognosis in ovarian cancer.

High recurrence rate and platinum resistance are the major causes of poor prognosis in ovarian cancer (OC). Elucidating the pathogenic mechanisms of recurrence and platinum resistance is essential for early prevention of OC recurrence and the development of novel intervention strategies. In this study, we found that high protein acetylation in recurrent ovarian cancer (ROC) is closely associated with high expression of the orphan G protein-coupled receptor GPRC5A. GPRC5A represents a potential poor prognostic factor for OC. GPRC5A undergoes acetylation and deacetylation modification at K348 by CREBBP and SIRT5, respectively, and the acetylated GPRC5A escapes from lysosome degradation to be stabilized. High expression of GPRC5A activates the PI3K-AKT signaling pathway to induce cisplatin resistance in ovarian cancer, while inhibition of AKT abolishes the GPRC5A-induced cisplatin resistance. Consistently, acetylation and deacetylation of GPRC5A at K348 by CREBBP and SIRT5 profoundly affect the cisplatin sensitivity as well as the ovarian tumorigenesis in mice bearing xenografts of SK-OV-3 ovarian cancer cells, respectively, and acetyl-K348-GPRC5A expression positively correlates with the poor prognosis of OC by analyzing the pathological sections and clinical data. Taken together, the present study identifies the GPRC5A acetylation at K348 and its stabilization as a hitherto uncharacterized mechanism controlling cisplatin resistance and OC recurrence, and may shed light on the early biomarker of OC recurrence and potential target for therapeutic intervention of chemoresistance of this malignancy.