PPM1H is down-regulated by ATF6 and dephosphorylates p-RPS6KB1 to inhibit progression of hepatocellular carcinoma

Xiaoshuang Yang; Jianting Guo; Wei Li; Chunrui Li; Xilin Zhu; Ying Liu; Xiaopan Wu

doi:10.1016/j.omtn.2023.06.013

PPM1H is down-regulated by ATF6 and dephosphorylates p-RPS6KB1 to inhibit progression of hepatocellular carcinoma

Mol Ther Nucleic Acids. 2023 Jun 19:33:164-179. doi: 10.1016/j.omtn.2023.06.013. eCollection 2023 Sep 12.

Authors

Xiaoshuang Yang^{1

2}, Jianting Guo^{1

2}, Wei Li³, Chunrui Li⁴, Xilin Zhu^{1

2}, Ying Liu^{1

2}, Xiaopan Wu^{1

2}

Affiliations

¹ State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing 100005, P.R. China.
² School of Basic Medicine, Peking Union Medical College, Beijing 100005, P.R. China.
³ Department of Interventional Radiology, Affiliated Hospital of Qingdao University, Shandong 266003, P.R. China.
⁴ Beijing Cloud Computing Key Technique and Application Key Laboratory, Beijing Computing Center, Beijing 100094, P.R. China.

Abstract

We have shown previously that polymorphism of activating transcription factor 6 (ATF6) is associated with susceptibility to hepatocellular carcinoma (HCC). Therefore, genes down-regulated by ATF6 might play a tumor-suppressing role. In the present study, we identified that expression of protein phosphatase magnesium- or manganous-dependent 1H (PPM1H) mRNA and protein can be inhibited by ATF6 in hepatoma cells and mice with liver Atf6 knockdown. Tumor tissues from 134 HCC patients were analyzed by immunohistochemistry, and PPM1H exhibited higher expression levels in adjacent para-cancer tissues than in HCC tissues. Therefore, patients with higher expression of PPM1H had a better prognosis. PPM1H inhibited proliferation, migration, and invasion of hepatoma cells. In addition, PPM1H inhibited induced HCC nodule formation as well as tumor xenograft growth in diethylnitrosamine/CCl₄-induced HCC mouse model and nude mouse tumorigenicity assay, respectively. A 3D model of PPM1H was obtained by homology multi-template modeling, and ribosomal protein S6 kinase B1 (RPS6KB1) in the bone morphogenetic protein (BMP)/transforming growth factor β (TGF-β) pathway was screened out as the potential substrate of PPM1H by Rosetta. PPM1H could directly dephosphorylate p-RPS6KB1. To conclude, we discovered RPS6KB1 as a new PPM1H dephosphorylation substrate. PPM1H exhibited a suppressive effect on HCC progression by dephosphorylating p-RPS6KB1.

Keywords: ATF6; MT: RNA/DNA Editing; RPS6KB1; hepatocellular carcinoma; homology modeling; protein phosphatase 1H.