p53 mitigates the effects of oncogenic HRAS in urothelial cells via the repression of .

Inhibition of TRPML1, which is encoded by , is known to deter cell proliferation in various malignancies. Here, we report that the tumor suppressor, p53, represses in the urothelium such that either the constitutive loss or ectopic knockdown of -in both healthy and bladder cancer cells-increased expression. Conversely, nutlin-mediated activation of p53 led to the repression of . Elevated expression in p53-deficient cancer cells, though not sufficient for bolstering proliferation, augmented the effects of oncogenic HRAS on proliferation, cytokine production, and invasion. Our data suggest that owing to derepression of , urothelial cells lacking p53 are poised for tumorigenesis driven by oncogenic HRAS. Given our prior findings that mutations predict addiction to TRPML1, this study points to the utility of TRPML1 inhibitors for mitigating the growth of a subset of urothelial tumors that lack p53.