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Elevated MCOLN1 Expression in p53-Deficient Bladder Cancer is Necessary for Oncogene-Induced Cell proliferation, Inflammation, and Invasion

Jewon Jung; Han Liao; Hong Liang; John F. Hancock; Catherine Denicourt; Kartik Venkatachalam

2020-07-09 cancer biology
10.1101/2020.07.08.193862 bioRxiv
Show abstract

Inhibition of the endolysosomal cation channel, TRPML1, which is encoded by MCOLN1, deters the proliferation of cancer cells with augmented TFEB activity. Here, we report that the tumor suppressor, p53, antagonizes TFEB-driven MCOLN1 expression in bladder cancer. Not only was the constitutive loss of p53 in bladder cancer cells associated with higher MCOLN1 mRNA, knockdown of TP53 in lines with wild type alleles of the tumor suppressor increased MCOLN1 expression. Elevated TRPML1 abundance in p53-deficient cancer cells, although not sufficient for bolstering proliferation, was necessary for the effects of oncogenic HRAS on cell division, cytokine production, and invasion. These data demonstrate that hyperactivation of the TFEB- MCOLN1 transcriptional axis in urothelial cells lacking p53 permits tumorigenesis stemming from HRAS mutations. Furthermore, the insight that loss of p53 predicts addiction to TRPML1 informs an actionable therapeutic strategy for bladder cancer.

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