PDLIM1 Inhibits Tumor Metastasis Through Activating Hippo Signaling in Hepatocellular Carcinoma.

Hepatology (Baltimore, Md.) 2020 May

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Tumor metastasis is a major factor of high recurrence and mortality in hepatocellular carcinoma (HCC), but its underlying mechanism remains elusive. We report that PDZ and LIM domain protein 1 (PDLIM1) is significantly down-regulated in metastatic human HCC tissues, which predicts unfavorable prognosis, suggesting that PDLIM1 may play an important inhibitory role during HCC metastasis. Functional studies indicate that PDLIM1 knockdown induces epithelial-to-mesenchymal transition (EMT) of HCC cells, elevates their invasive capacity, and promotes metastasis in vitro and in vivo, whereas overexpression of PDLIM1 exhibits opposite phenotypes. Mechanistically, PDLIM1 competitively binds to the cytoskeleton cross-linking protein alpha-actinin 4 (ACTN4), leading to the disassociation of ACTN4 from F-actin, thus preventing F-actin overgrowth. In contrast, loss of PDLIM1 induces excessive F-actin formation, resulting in dephosphorylation of large tumor suppressor kinase 1 and activation of Yes-associated protein, thereby promoting HCC metastasis. Moreover, Asn145 (N145) of PDLIM1 is critical for its interaction with ACTN4, and N145A mutation abolishes its regulatory function in Hippo signaling and HCC metastasis. Our findings indicate that PDLIM1 suppresses HCC metastasis by modulating Hippo signaling, suggesting that PDLIM1 may be a potential prognostic marker for metastatic HCC. © 2020 by the American Association for the Study of Liver Diseases.

Citation

Zhao Huang, Jian-Kang Zhou, Kui Wang, Haining Chen, Siyuan Qin, Jiayang Liu, Maochao Luo, Yan Chen, Jingwen Jiang, Li Zhou, Lei Zhu, Juan He, Jiao Li, Wenchen Pu, Yanqiu Gong, Jianbo Li, Qin Ye, Dandan Dong, Hongbo Hu, Zongguang Zhou, Lunzhi Dai, Canhua Huang, Xiawei Wei, Yong Peng. PDLIM1 Inhibits Tumor Metastasis Through Activating Hippo Signaling in Hepatocellular Carcinoma. Hepatology (Baltimore, Md.). 2020 May;71(5):1643-1659