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CK2-induced cooperation of HHEX with the YAP-TEAD4 complex promotes colorectal tumorigenesis
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CK2-induced cooperation of HHEX with the YAP-TEAD4 complex promotes colorectal tumorigenesis
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CK2-induced cooperation of HHEX with the YAP-TEAD4 complex promotes colorectal tumorigenesis
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Journal Article
CK2-induced cooperation of HHEX with the YAP-TEAD4 complex promotes colorectal tumorigenesis
2022
Overview
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.
Hippo signalling is often deregulated in cancers. Here the authors show that CK2 enhances the cooperation of HHEX with YAP-TEAD complex to promote colorectal tumorigenesis.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
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/ 13/106
/ 13/109
/ 13/51
/ 13/89
/ 14
/ 14/1
/ 38
/ 38/15
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/ 38/90
/ 38/91
/ 42
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/ 45/88
/ 64
/ 64/60
/ 82/58
/ Cancer
/ Casein
/ Casein Kinase II - metabolism
/ Colorectal Neoplasms - metabolism
/ Colorectal Neoplasms - pathology
/ DNA-Binding Proteins - genetics
/ DNA-Binding Proteins - metabolism
/ Genes
/ Homeobox
/ Homeodomain Proteins - metabolism
/ Humanities and Social Sciences
/ Humans
/ Kinases
/ Muscle Proteins - metabolism
/ Science
/ TEA Domain Transcription Factors - metabolism
/ Transcription Factors - metabolism
