Targeting Pin1 by inhibitor API-1 regulates microRNA biogenesis and suppresses hepatocellular carcinoma development
Targeting Pin1 by inhibitor API-1 regulates microRNA biogenesis and suppresses hepatocellular carcinoma development
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通过抑制剂 API-1 靶向 Pin1 可调节 microRNA 生物合成并抑制肝细胞癌的发展
DOI：
10.1002/hep.29819
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发表时间：
2018-08-01
期刊：
影响因子：
13.5
通讯作者：
Peng, Yong
中科院分区：
文献类型：
--
作者：
Pu, Wenchen;Li, Jiao;Peng, Yong
肝细胞癌（HCC）是世界范围内癌症死亡的主要原因，但有效的治疗方法很少。异常microRNA（miRNA）生物发生与HCC发展相关。我们以前证明，肽基脯氨酰顺反异构酶NIMA相互作用1（Pin 1）参与miRNA的生物合成，是一个潜在的肝癌治疗靶点。然而，Pin 1如何调节miRNA生物发生仍然不清楚。在这里，我们提出了体内证据表明Pin 1过表达与HCC的发展直接相关。Pin 1抑制剂（API-1）是一种靶向Pin 1肽基-脯氨酰异构酶结构域并抑制Pin 1顺反异构化活性的特异性小分子，其给药可抑制HCC细胞的体外细胞增殖和迁移。但API-1诱导的Pin 1抑制对Pin 1表达低和/或XPO 5磷酸化低的HCC细胞不敏感。在机制上，Pin 1识别并异构化磷酸化XPO 5的磷酸化丝氨酸-脯氨酸基序，并钝化磷酸化XPO 5。通过API-1抑制Pin 1可维持磷酸化XPO 5的活性构象，并恢复XPO 5驱动的前体miRNA核-细胞质输出，激活抗癌miRNA生物合成，并导致体外HCC抑制和异种移植小鼠中HCC抑制。结论：实验证据表明，通过API-1抑制Pin 1通过保持活性XPO 5构象上调miRNA生物合成并抑制HCC发展，揭示了Pin 1介导的miRNA生物合成的机制，并明确支持API-1作为HCC治疗的候选药物，特别是对于Pin 1过表达的细胞外信号调节激酶激活的HCC。（Hepatology 2018）。
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 peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (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 the Pin1 inhibitor (API-1), a specific small molecule targeting Pin1 peptidyl-prolyl isomerase 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 exportin-5 (XPO5) phosphorylation. Mechanistically, Pin1 recognizes and isomerizes the phosphorylated serine-proline motif of phosphorylated XPO5 and passivates phosphorylated XPO5. Pin1 inhibition by API-1 maintains the active conformation of phosphorylated XPO5 and 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 that Pin1 inhibition by API-1 up-regulates miRNA biogenesis by retaining active XPO5 conformation and suppresses HCC development, revealing the mechanism of Pin1-mediated miRNA biogenesis and unequivocally supporting API-1 as a drug candidate for HCC therapy, especially for Pin1-overexpressing, extracellular signal-regulated kinase-activated HCC. (Hepatology 2018).