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CK2 诱导 HHEX 与 YAP-TEAD4 复合物合作促进结直肠肿瘤发生。

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

机构信息

Department of Colorectal and Anal Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China.

Shanghai Colorectal Cancer Research Center, Shanghai, 200092, China.

出版信息

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

DOI:10.1038/s41467-022-32674-6
PMID:36008411
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9411202/
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.

摘要

Hippo 通路失调导致 YAP-TEAD 转录复合物在各种癌症中过度激活，包括结直肠癌（CRC）。在这项研究中，我们观察到 HHEX（造血表达同源盒）可能增强 YAP-TEAD 复合物的转录活性。HHEX 与 YAP-TEAD 复合物结合并稳定其在调节基因组位置，共同调节一组 YAP/TEAD 靶基因的表达。此外，HHEX 还可以通过控制 YAP/TAZ 的表达间接调节这些靶基因。重要的是，HHEX 是 YAP 在 CRC 进展过程中促进肿瘤发生的必需因子。在血清刺激下，CK2（酪蛋白激酶 2）磷酸化 HHEX 并增强其与 TEAD4 的相互作用。CK2 抑制剂 CX-4945 减少 HHEX 与 TEAD4 之间的相互作用，导致 YAP/TEAD 靶基因的表达减少。CX-4945 与 YAP-TEAD 抑制剂 verteporfin 和 Super-TDU 的抗肿瘤活性协同作用。HHEX 的高表达与 YAP/TEAD 的过度激活相关，并与 CRC 患者的不良预后相关。总之，我们的研究确定 HHEX 是 YAP/TEAD 的正调节剂，促进结直肠肿瘤发生，为 CRC 中靶向 YAP/TEAD 提供了新的治疗策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/024b/9411202/c0a7b5ebf241/41467_2022_32674_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/024b/9411202/d7c6b86e3ce1/41467_2022_32674_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/024b/9411202/fdd890a286e3/41467_2022_32674_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/024b/9411202/1cb8b545bf07/41467_2022_32674_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/024b/9411202/ef96137ceaac/41467_2022_32674_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/024b/9411202/8038cad17ef9/41467_2022_32674_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/024b/9411202/d1e3045f9b5b/41467_2022_32674_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/024b/9411202/d3fb5ebfc4fd/41467_2022_32674_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/024b/9411202/c0a7b5ebf241/41467_2022_32674_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/024b/9411202/d7c6b86e3ce1/41467_2022_32674_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/024b/9411202/fdd890a286e3/41467_2022_32674_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/024b/9411202/1cb8b545bf07/41467_2022_32674_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/024b/9411202/ef96137ceaac/41467_2022_32674_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/024b/9411202/8038cad17ef9/41467_2022_32674_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/024b/9411202/d1e3045f9b5b/41467_2022_32674_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/024b/9411202/d3fb5ebfc4fd/41467_2022_32674_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/024b/9411202/c0a7b5ebf241/41467_2022_32674_Fig8_HTML.jpg

相似文献

[1]
CK2-induced cooperation of HHEX with the YAP-TEAD4 complex promotes colorectal tumorigenesis.

Nat Commun. 2022-8-25

[2]
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[3]
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[4]
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[5]
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[6]
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[7]
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[8]
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[10]
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J Transl Med. 2025-8-18

[2]
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Ann Med. 2025-12

[3]
Extracellular Matrix Signaling Cues: Biological Functions, Diseases, and Therapeutic Targets.

MedComm (2020). 2025-7-17

[4]
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Front Oncol. 2025-6-19

[5]
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Oncogene. 2025-7-2

[6]
VCPIP1 facilitates pancreatic adenocarcinoma progression via Hippo/YAP signaling.

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[7]
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Adv Sci (Weinh). 2025-5

[8]
The Role of Yes-Associated Protein in Inflammatory Diseases and Cancer.

MedComm (2020). 2025-3-10

[9]
YAP/TAZ-associated cell signaling - at the crossroads of cancer and neurodevelopmental disorders.

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[10]
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iScience. 2025-1-7

本文引用的文献

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Trends Cancer. 2020-9

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Oncogene. 2020-5-12

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