p53 mitigates the effects of oncogenic HRAS in urothelial cells via the repression of MCOLN1.

Inhibition of TRPML1, which is encoded by MCOLN1, is known to deter cell proliferation in various malignancies. Here, we report that the tumor suppressor, p53, represses MCOLN1 in the urothelium such that either the constitutive loss or ectopic knockdown of TP53-in both healthy and bladder cancer cells-increased MCOLN1 expression. Conversely, nutlin-mediated activation of p53 led to the repression of MCOLN1. Elevated MCOLN1 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 MCOLN1, urothelial cells lacking p53 are poised for tumorigenesis driven by oncogenic HRAS. Given our prior findings that HRAS 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.