Targeting Pin1 by inhibitor API-1 regulates microRNA biogenesis and suppresses hepatocellular carcinoma development

Abstract

Hepatocellular carcinoma (HCC) is a leading cause of cancer death worldwide, but there are few effective treatments. Aberrant microRNA (miRNA) biogenesis is correlated with HCC development. We previously demonstrated that prolyl isomerase Pin1 participates in miRNA biogenesis and is a potential HCC treatment target. However, how Pin1 modulates miRNA biogenesis remains obscure. Here, we present in vivo evidence that Pin1 overexpression is directly linked to the development of HCC. Administration with Pin1 inhibitor API-1, a novel and specific small molecule targeting Pin1 PPIase domain and inhibiting Pin1 cis-trans isomerizing activity, suppresses in vitro cell proliferation and migration of HCC cells. But API-1-induced Pin1 inhibition is insensitive to HCC cells with low Pin1 expression and/or low XPO5 phosphorylation. Mechanistically, Pin1 recognizes and isomerizes the phosphorylated Serine-Proline (pS-P) motif of pXPO5 and passivates pXPO5. Pin1 inhibition by API-1 maintains the active conformation of pXPO5, restores XPO5-driven precursor miRNA nuclear-to-cytoplasm export, activating anticancer miRNA biogenesis, and leading to both in vitro HCC suppression and HCC suppression in xenograft mice. Conclusion: Experimental evidence suggests Pin1 inhibition by API-1 upregulates miRNA biogenesis via retaining active XPO5 conformation and suppresses HCC development, revealing the mechanism of Pin1-mediated miRNA biogenesis and unequivocally supports API-1 as a novel drug candidate for HCC therapy, especially for Pin1-overexpressing, ERK-activated HCC. This article is protected by copyright. All rights reserved.

http://ift.tt/2nqHFxH