Journal Article

TUBB4A interacts with MYH9 to protect the nucleus during cell migration and promotes prostate cancer via GSK3β/β-catenin signalling

Wei, Shi, Bae, Sejong, Sonpavde, Guru, Liu, Zhicao, Xu, Zhifang, Liu, Runhua, Ye, Ping, Wang, Shuaibin, Naik, Gurudatta A., Zhang, Chao, Jiao, Kai, Rais-Bahrami, Soroush, Zhao, Zhiying, Wang, Lizhong, Yi, Baozhu, Gao, Song, Yang, Wei-Hsiung

2022

Overview

Human tubulin beta class IVa (TUBB4A) is a member of the β-tubulin family. In most normal tissues, expression of TUBB4A is little to none, but it is highly expressed in human prostate cancer. Here we show that high expression levels of TUBB4A are associated with aggressive prostate cancers and poor patient survival, especially for African-American men. Additionally, in prostate cancer cells, TUBB4A knockout (KO) reduces cell growth and migration but induces DNA damage through increased γH2AX and 53BP1. Furthermore, during constricted cell migration, TUBB4A interacts with MYH9 to protect the nucleus, but either TUBB4A KO or MYH9 knockdown leads to severe DNA damage and reduces the NF-κB signaling response. Also, TUBB4A KO retards tumor growth and metastasis. Functional analysis reveals that TUBB4A/GSK3β binds to the N-terminal of MYH9, and that TUBB4A KO reduces MYH9-mediated GSK3β ubiquitination and degradation, leading to decreased activation of β-catenin signaling and its relevant epithelial-mesenchymal transition. Likewise, prostate-specific deletion of Tubb4a reduces spontaneous tumor growth and metastasis via inhibition of NF-κB, cyclin D1, and c-MYC signaling activation. Our results suggest an oncogenic role of TUBB4A and provide a potentially actionable therapeutic target for prostate cancers with TUBB4A overexpression. The β-tubulin family protein TUBB4A is highly expressed in cancer but it’s molecular role is unclear. Here, the authors show that TUBB4A is required to protect the nucleus from genomic instability during migration and that it’s over expression promotes cancer progression.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/1 / 13/109 / 13/2 / 13/31 / 13/51 / 13/89 / 14/1 / 14/19 / 14/5 / 38/1 / 45/77 / 631/67/322 / 631/67/589/466 / 64/60 / 692/4025/1752 / 82/51 / 82/80 / beta Catenin - genetics / beta Catenin - metabolism / c-Myc protein / Cell adhesion & migration / Cell Line, Tumor / Cell migration / Cell Movement - genetics / Cell Proliferation - genetics / Cyclin D1 / Damage / Deoxyribonucleic acid / DNA / DNA damage / Epithelial-Mesenchymal Transition - genetics / Functional analysis / Genomic instability / Glycogen Synthase Kinase 3 beta - genetics / Glycogen Synthase Kinase 3 beta - metabolism / Humanities and Social Sciences / Humans / Male / Mesenchyme / Metastases / Metastasis / multidisciplinary / Myc protein / Myosin Heavy Chains - genetics / Myosin Heavy Chains - metabolism / NF-kappa B - metabolism / NF-κB protein / Nuclei (cytology) / Prostate cancer / Prostatic Neoplasms - pathology / Proto-Oncogene Proteins c-myc - genetics / Proto-Oncogene Proteins c-myc - metabolism / Science / Science (multidisciplinary) / Signal Transduction / Signaling / Therapeutic targets / Tubulin / Tubulin - metabolism / Tumors / Ubiquitination / β-Catenin