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; Chen-Ying Liu

doi:10.1038/s41467-022-32674-6

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

Nat Commun. 2022 Aug 25;13(1):4995. doi: 10.1038/s41467-022-32674-6.

Authors

Yuegui Guo^#^{1

2}, Zhehui Zhu^#^{1

2

3}, Zhenyu Huang^{1

2}, Long Cui^{1

2}, Wei Yu³, Wanjin Hong⁴, Zhaocai Zhou⁵, Peng Du^{6

7}, Chen-Ying Liu^{8

9}

Affiliations

¹ Department of Colorectal and Anal Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China.
² Shanghai Colorectal Cancer Research Center, Shanghai, 200092, China.
³ State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai, 200438, China.
⁴ Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), 61, Biopolis Drive, Proteos, Singapore, 138673, Singapore.
⁵ State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai, 200438, China. zhouzhaocai@fudan.edu.cn.
⁶ Department of Colorectal and Anal Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China. dupeng@xinhuamed.com.cn.
⁷ Shanghai Colorectal Cancer Research Center, Shanghai, 200092, China. dupeng@xinhuamed.com.cn.
⁸ Department of Colorectal and Anal Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China. liuchenying@xinhuamed.com.cn.
⁹ Shanghai Colorectal Cancer Research Center, Shanghai, 200092, China. liuchenying@xinhuamed.com.cn.

^# Contributed equally.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Carcinogenesis
Casein Kinase II* / genetics
Casein Kinase II* / metabolism
Colorectal Neoplasms* / metabolism
Colorectal Neoplasms* / pathology
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism
Homeodomain Proteins / metabolism
Humans
Muscle Proteins / metabolism
TEA Domain Transcription Factors / metabolism*
Transcription Factors / metabolism
YAP-Signaling Proteins / metabolism*

Substances

DNA-Binding Proteins
HHEX protein, human
Homeodomain Proteins
Muscle Proteins
TEA Domain Transcription Factors
TEAD4 protein, human
Transcription Factors
YAP-Signaling Proteins
Casein Kinase II