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

• Published in: Oncogene Vol. 40; no. 19; pp. 3394 - 3407
• Main Authors: Liu, Jiayang, Huang, Zhao, Chen, Hai-Ning, Qin, Siyuan, Chen, Yan, Jiang, Jingwen, Zhang, Zhe, Luo, Maochao, Ye, Qin, Xie, Na, Zhou, Zong-Guang, Wei, Yuquan, Xie, Ke, Huang, Canhua
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13.05.2021; Nature Publishing Group
• Subjects: 13/109; 14/19; 38/47; 631/67/322; 692/53/2422; 96/95; ADAM Proteins - genetics; ADAM Proteins - metabolism; Animals; Apoptosis; Cancer; Cancer-Associated Fibroblasts - metabolism; Cancer-Associated Fibroblasts - pathology; Cell Biology; Cell Line, Tumor; Cell Movement - physiology; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Disease Progression; Fibroblasts; Heterografts; Human Genetics; Humans; Internal Medicine; Kruppel-Like Transcription Factors - genetics; Kruppel-Like Transcription Factors - metabolism; Male; Medicine; Medicine & Public Health; Membrane Proteins; Metastases; Metastasis; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Metastasis; Oncology; Serine Endopeptidases; Survival Rate; Transcription; Transforming Growth Factor beta - genetics; Transforming Growth Factor beta - metabolism; Tumor Microenvironment
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-021-01713-9

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.