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

Author

Listed:
  • Song Gao

    (University of Alabama at Birmingham)

  • Shuaibin Wang

    (University of Alabama at Birmingham)

  • Zhiying Zhao

    (University of Alabama at Birmingham)

  • Chao Zhang

    (University of Alabama at Birmingham)

  • Zhicao Liu

    (University of Alabama at Birmingham)

  • Ping Ye

    (University of Alabama at Birmingham)

  • Zhifang Xu

    (University of Alabama at Birmingham)

  • Baozhu Yi

    (University of Alabama at Birmingham)

  • Kai Jiao

    (University of Alabama at Birmingham)

  • Gurudatta A. Naik

    (University of Alabama at Birmingham)

  • Shi Wei

    (University of Alabama at Birmingham
    University of Alabama at Birmingham)

  • Soroush Rais-Bahrami

    (University of Alabama at Birmingham
    University of Alabama at Birmingham
    University of Alabama at Birmingham)

  • Sejong Bae

    (University of Alabama at Birmingham
    University of Alabama at Birmingham)

  • Wei-Hsiung Yang

    (Mercer University School of Medicine)

  • Guru Sonpavde

    (Dana Farber Cancer Institute)

  • Runhua Liu

    (University of Alabama at Birmingham
    University of Alabama at Birmingham)

  • Lizhong Wang

    (University of Alabama at Birmingham
    University of Alabama at Birmingham)

Abstract

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.

Suggested Citation

  • Song Gao & Shuaibin Wang & Zhiying Zhao & Chao Zhang & Zhicao Liu & Ping Ye & Zhifang Xu & Baozhu Yi & Kai Jiao & Gurudatta A. Naik & Shi Wei & Soroush Rais-Bahrami & Sejong Bae & Wei-Hsiung Yang & Gu, 2022. "TUBB4A interacts with MYH9 to protect the nucleus during cell migration and promotes prostate cancer via GSK3β/β-catenin signalling," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30409-1
    DOI: 10.1038/s41467-022-30409-1
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