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ZNF37A promotes tumor metastasis through transcriptional control of THSD4/TGF-β axis in colorectal cancer

Oncogene volume 40, pages 3394–3407 (2021)Cite this article

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Abstract

Poorly differentiated colorectal cancer (CRC) is characterized by aggressive invasion and stromal fibroblast activation, which results in rapid progression and poor therapeutic consequences. However, the regulatory mechanism involved remains unclear. Here, we showed that ZNF37A, a member of KRAB-ZFP family, was upregulated in poorly differentiated CRCs and associated with tumor metastasis. ZNF37A enhanced the metastatic potential of multiple CRC cell lines and promoted distant metastasis in an orthotopic CRC model. Further investigation attributed the ZNF37A-exacerbated metastasis to increased extracellular TGF-β and the consequent activation of cancer-associated fibroblasts (CAFs) in tumor microenvironment (TME). Mechanistically, ZNF37A formed a complex with KAP1 and bound to the promoter of THSD4, a TME modulator, to suppress its transcription, which is required for ZNF37A-mediated TGF-β activation and CRC metastasis. Collectively, our study indicates that ZNF37A promotes TGF-β signaling in CRC cells and activates CAFs by transcriptionally repressing THSD4 to drive CRC metastasis, implicating ZNF37A as a potential biomarker for CRC differentiation and progression.

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Fig. 1: ZNF37A is upregulated in human colorectal cancers and associated with poor-prognosis subtype.
Fig. 2: ZNF37A promotes colorectal cancer cell invasion and metastasis in vitro and in vivo.
Fig. 3: ZNF37A activates TGF-β signaling to promote colorectal cancer metastasis.
Fig. 4: ZNF37A promotes the positive feedback regulation between cancer cells and cancer-associated fibroblasts.
Fig. 5: ZNF37A directly binds to THSD4 promoter and represses THSD4 transcription.
Fig. 6: THSD4 is a downstream effector of ZNF37A.

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Acknowledgements

This work was supported by grants from Guangdong Basic and Applied Basic Research Foundation (2019B030302012), National Key R&D Program of China (2020YFA0509400, 2020YFC2002700), the Chinese NSFC (nos 81821002, 81672867, 81790251, 81702378) and China Postdoctoral Science Foundation (2019T120845, 2018M643496).

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Author notes

  1. These authors contributed equally: Jiayang Liu, Zhao Huang, Hai-Ning Chen.

Authors and Affiliations

  1. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, P.R. China

    Jiayang Liu, Zhao Huang, Siyuan Qin, Yan Chen, Jingwen Jiang, Zhe Zhang, Maochao Luo, Yuquan Wei & Canhua Huang

  2. Department of Gastrointestinal Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China

    Hai-Ning Chen & Zong-Guang Zhou

  3. Department of Oncology, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China

    Qin Ye & Ke Xie

  4. West China School of Basic Medical Sciences & Forensic Medicine, and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, P.R. China

    Na Xie

  5. School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China

    Canhua Huang

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Contributions

CH, ZZ, and YW designed and supervised the research. JL, ZH, QY, YC, JJ, ZZ, KX, and ML performed the experiments. HC performed the bioinformatic analysis. SQ, NX, and JL developed the animal models. QY, YW, KX, and ZZ provided the clinic samples. ZH, HC, and CH wrote the manuscript.

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Correspondence to Ke Xie or Canhua Huang.

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Liu, J., Huang, Z., Chen, HN. et al. ZNF37A promotes tumor metastasis through transcriptional control of THSD4/TGF-β axis in colorectal cancer. Oncogene 40, 3394–3407 (2021). https://doi.org/10.1038/s41388-021-01713-9

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