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CK2-induced cooperation of HHEX with the YAP-TEAD4 complex promotes colorectal tumorigenesis

Author

Listed:
  • Yuegui Guo

    (Shanghai Jiao Tong University School of Medicine
    Shanghai Colorectal Cancer Research Center)

  • Zhehui Zhu

    (Shanghai Jiao Tong University School of Medicine
    Shanghai Colorectal Cancer Research Center
    Fudan University)

  • Zhenyu Huang

    (Shanghai Jiao Tong University School of Medicine
    Shanghai Colorectal Cancer Research Center)

  • Long Cui

    (Shanghai Jiao Tong University School of Medicine
    Shanghai Colorectal Cancer Research Center)

  • Wei Yu

    (Fudan University)

  • Wanjin Hong

    (Technology and Research (A*STAR))

  • Zhaocai Zhou

    (Fudan University)

  • Peng Du

    (Shanghai Jiao Tong University School of Medicine
    Shanghai Colorectal Cancer Research Center)

  • Chen-Ying Liu

    (Shanghai Jiao Tong University School of Medicine
    Shanghai Colorectal Cancer Research Center)

Abstract

Dysregulation of Hippo pathway leads to hyperactivation of YAP-TEAD transcriptional complex in various cancers, including colorectal cancer (CRC). In this study, we observed that HHEX (Hematopoietically expressed homeobox) may enhance transcription activity of the YAP-TEAD complex. HHEX associates with and stabilizes the YAP-TEAD complex on the regulatory genomic loci to coregulate the expression of a group of YAP/TEAD target genes. Also, HHEX may indirectly regulate these target genes by controlling YAP/TAZ expression. Importantly, HHEX is required for the pro-tumorigenic effects of YAP during CRC progression. In response to serum stimulation, CK2 (Casein Kinase 2) phosphorylates HHEX and enhances its interaction with TEAD4. A CK2 inhibitor CX-4945 diminishes the interaction between HHEX and TEAD4, leading to decreased expression of YAP/TEAD target genes. CX-4945 synergizes the antitumor activity of YAP-TEAD inhibitors verteporfin and Super-TDU. Elevated expression of HHEX is correlated with hyperactivation of YAP/TEAD and associated with poor prognosis of CRC patients. Overall, our study identifies HHEX as a positive modulator of YAP/TEAD to promote colorectal tumorigenesis, providing a new therapeutic strategy for targeting YAP/TEAD in CRC.

Suggested Citation

  • Yuegui Guo & Zhehui Zhu & Zhenyu Huang & Long Cui & Wei Yu & Wanjin Hong & Zhaocai Zhou & Peng Du & Chen-Ying Liu, 2022. "CK2-induced cooperation of HHEX with the YAP-TEAD4 complex promotes colorectal tumorigenesis," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32674-6
    DOI: 10.1038/s41467-022-32674-6
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    References listed on IDEAS

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    1. Shi Jiao & Chuanchuan Li & Qian Hao & Haofei Miao & Lei Zhang & Lin Li & Zhaocai Zhou, 2017. "VGLL4 targets a TCF4–TEAD4 complex to coregulate Wnt and Hippo signalling in colorectal cancer," Nature Communications, Nature, vol. 8(1), pages 1-13, April.
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