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

Yuegui Guo, Zhehui Zhu, Zhenyu Huang, Long Cui, Wei Yu, Wanjin Hong, Zhaocai Zhou (), Peng Du () and Chen-Ying Liu ()
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Yuegui Guo: Shanghai Jiao Tong University School of Medicine
Zhehui Zhu: Shanghai Jiao Tong University School of Medicine
Zhenyu Huang: Shanghai Jiao Tong University School of Medicine
Long Cui: Shanghai Jiao Tong University School of Medicine
Wei Yu: Fudan University
Wanjin Hong: Technology and Research (A*STAR)
Zhaocai Zhou: Fudan University
Peng Du: Shanghai Jiao Tong University School of Medicine
Chen-Ying Liu: Shanghai Jiao Tong University School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-32674-6

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