Journal Article

PTENα and PTENβ promote carcinogenesis through WDR5 and H3K4 trimethylation

Zhang, Cheng, Ji, Yan, Chen, Guo-Qiang, Xia, Qiang, Zhang, Na, He, Ping, Yu, Yun, Yu, Jian-Xiu, Zheng, Jun-Ke, Ge, Meng-Kai, Dong, Shuang-Shu, Yang, Shuo, Shen, Shao-Ming, Xia, Li

2019

Overview

PTENα and PTENβ are two longer translational variants of phosphatase and tensin homolog (PTEN) messenger RNA. Their expressional regulations and functions in carcinogenesis remain largely unknown. Here, we demonstrate that, in contrast with the well-established tumour-suppressive role of canonical PTEN, PTENα and PTENβ promote tumourigenesis by directly interacting with the histone H3 lysine 4 (H3K4) presenter WDR5 to promote H3K4 trimethylation and maintain a tumour-promoting signature. We also show that USP9X and FBXW11 bind to the amino-terminal extensions of PTENα/β, and respectively deubiquitinate and ubiquitinate lysines 235 and 239 in PTENα to regulate PTENα/β stability. In accordance, USP9X promotes tumourigenesis and FBXW11 suppresses tumourigenesis through PTENα/β. Taken together, our results indicate that the Pten gene is a double-edged sword for carcinogenesis, and reinterpretation of the importance of the Pten gene in carcinogenesis is warranted. Shen et al. show that PTENα/β stability is regulated through a ubiquitin-dependent mechanism mediated by USP9X and FBXW11 to modulate H3K4 trimethylation through WDR5 and promote tumour development.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13 / 13/1 / 13/105 / 13/51 / 14 / 14/35 / 38 / 38/91 / 45 / 631/208/69 / 631/337/474/582 / 631/67 / 631/67/1244 / 64 / 64/60 / 82 / 82/47 / 82/58 / 96 / 96/109 / Animals / beta-Transducin Repeat-Containing Proteins - genetics / beta-Transducin Repeat-Containing Proteins - metabolism / Biomedical and Life Sciences / Cancer Research / Carcinogenesis / Carcinogenesis - genetics / Carcinogenesis - metabolism / Carcinogenesis - pathology / Carcinogens / Carcinoma, Hepatocellular - genetics / Carcinoma, Hepatocellular - metabolism / Carcinoma, Hepatocellular - mortality / Carcinoma, Hepatocellular - pathology / Cell Biology / Cell Line, Tumor / Cell Movement / Cell Proliferation / Developmental Biology / Female / Gene Expression Regulation, Neoplastic / Histone H3 / Histones - genetics / Histones - metabolism / Homology / Humans / Intracellular Signaling Peptides and Proteins - genetics / Intracellular Signaling Peptides and Proteins - metabolism / Isoenzymes - genetics / Isoenzymes - metabolism / Life Sciences / Liver - metabolism / Liver - pathology / Liver Neoplasms - genetics / Liver Neoplasms - metabolism / Liver Neoplasms - mortality / Liver Neoplasms - pathology / Lysine / Male / Mice / Mice, Nude / mRNA / Proteolysis / PTEN Phosphohydrolase - genetics / PTEN Phosphohydrolase - metabolism / PTEN protein / Signal Transduction / Stem Cells / Survival Analysis / Tensin / Tumorigenesis / Tumors / Ubiquitin Thiolesterase - genetics / Ubiquitin Thiolesterase - metabolism / Ubiquitin-Protein Ligases - genetics / Ubiquitin-Protein Ligases - metabolism / Xenograft Model Antitumor Assays