GAMT facilitates tumor progression via inhibiting p53 in clear cell renal cell carcinoma.

Background: Clear cell renal cell carcinoma (ccRCC) is the most common type of RCC. Even though the targeted drugs for the treatment of ccRCC have a certain therapeutic effect, due to the problem of drug resistance, the search for new targets for targeted therapy of ccRCC remains urgent. GAMT is an enzyme involved in creatine metabolism. However, the precise biological roles and molecular mechanisms of GAMT in ccRCC are not fully understood.

Results: Here, we found that GAMT was upregulated in ccRCC cells and tissues and associated with poor prognosis. Further, GAMT has pro-oncogenic abilities in promoting ccRCC development and progression. Intriguingly, GAMT exerted biological functions independent of its role in catalyzing creatine synthesis. Mechanistically, GAMT overexpression contributes to the development and progression of ccRCC by inhibiting tumor suppressor p53. Finally, we identified fisetin as a novel GAMT inhibitor and validated its role in suppressing ccRCC progression and sensitizing ccRCC cells to targeted drug axitinib via in vivo and in vitro assays.

Conclusions: This study reveals that GAMT has pro-oncogenic abilities in promoting ccRCC development and progression. GAMT exerted its non-enzymatic functions possibly by regulating the expression of p53. Fisetin, the novel GAMT inhibitor identified herein, may serve as a new antitumor drug for ccRCC treatment.