Identities of functional pSer-Thr.Pro protein substrates of the PIN1 prolyl isomerase and its effects on downstream signaling in bladder carcinogenesis remain largely unknown. Phenotypically, we found that PIN1 positively regulated bladder cancer cell proliferation, cell motility, and urothelium clearance capacity in vitro and controlled tumor growth and potential metastasis in vivo. Mechanistically, we observed a negative enrichment of SREBP2-driven cholesterol metabolism pathways and a decrease in free/total cholesterol levels in PIN1-knockout bladder cancer cells. Moreover, we showed that PIN1 interacted with SREBP2 following its phosphorylation by the JNK MAP kinase at Ser455, which lies near the site-2 cleavage site that generates the active, nuclear form of SREBP2. Therapeutically, a combination of the covalent PIN1 inhibitor sulfopin and the HMGCoA reductase inhibitor simvastatin synergistically suppressed cell proliferation in vitro and tumor growth in vivo. Together, these findings emphasize that PIN1 can act as a driver and potential therapeutic target in bladder cancer.

Significance:

This study provides deeper insights into the regulatory role of the phospho–dependent prolyl isomerase PIN1 in bladder cancer. The identification of the link between PIN1 and SREBP2-mediated transcription and cholesterol biosynthesis offers the potential for developing novel therapeutic strategies for bladder cancer.

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