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HSF4 promotes tumor progression of colorectal cancer by transactivating c-MET

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Abstract

Heat shock factors (HSFs) are a family of transcription factors, composed of HSF1, HSF2, and HSF4, to regulate cell stress reaction for maintaining cellular homeostasis in response to adverse stimuli. Recent studies have disclosed the roles of HSF1 and HSF2 in modulating tumor development, including colorectal cancer (CRC). However, HSF4, which is closely associated with pathology of congenital cataracts, remains less studied in tumors. In this study, we aimed to describe the regulatory effects of HSF4 and underlying molecular mechanism in CRC progression. By bioinformatic analysis of TCGA database and TMA-IHC assay, we identified that the expression of HSF4 was significantly upregulated in CRCs compared with normal colonic tissues and was a prognostic factor of poor outcomes of CRC patients. Function assays, including CCK-8, colony formation, transwell assays, and xenografted mouse model, were employed to verify that HSF4 promoted cell growth, colony formation, invasion of CRC cells in vitro, and tumor growth in vivo as a potential oncogenic factor. Mechanistically, results of Chromatin immunoprecipitation (ChIP) and immunoblotting assays revealed that HSF4 associated directly to MET promoter to enhance expression of c-MET, a well-known oncogene in multiple cancers, thus fueling the activity of downstream ERK1/2 and AKT signaling pathways. In further rescue experiments, restoration of c-MET expression abolished inhibitory cell growth and invasion induced by downregulated HSF4 expression. To sum up, our findings describe a crucial role of HSF4 in CRC progression by enhancing activity of c-MET and downstream ERK1/2 and AKT signaling pathways, and highlight HSF4 as a potential therapeutic target for anti-CRC treatment.

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Data availability

The datasets used and/or analyzed in the current study are available from the corresponding author upon reasonable request.

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Funding

This study was supported by Grant from the National Natural Science Foundation of China (81860522, 81860509), Grant for Clinical Medical Center of Yunnan Provincial Health Commission (2020LCZXKF-XH02, 2021LCZXXF-XH03), and the Yunnan Medical Training Program (202205AC160070, 2018HB049, D-2017002).

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Authors and Affiliations

  1. Department of Medical Oncology, The First People’s Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and Technology, Kunming, 650000, China

    Wenjing Zhang

  2. Faculty of Medicine, Kunming University of Science and Technology, Kunming, 650000, China

    Wenjing Zhang, Xuelian Zhang & Peng Cheng

  3. Yunnan Digestive Endoscopy Clinical Medical Center, Department of Gastroenterology, The First People’s Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and Technology, 650000, Kunming, China

    Kelin Yue, Yan Li, Qiang Guo & Yu Zhang

  4. Department of Pathology, The First People’s Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and Technology, Kunming, 650000, China

    Ming Tang

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  1. Wenjing Zhang
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  2. Xuelian Zhang
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  3. Peng Cheng
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  4. Kelin Yue
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  5. Ming Tang
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  6. Yan Li
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  8. Yu Zhang
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Contributions

YZ and QG designed the study. WZ, XZ, and PC performed most of the assays in the research. KY and YL performed the bioinformatic analysis. MT evaluated and scored the intensity of IHC staining. YZ analyzed the data statistically and wrote the manuscript.

Corresponding author

Correspondence to Yu Zhang.

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The authors declare no competing interests.

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All related experiments were approved by the Ethics Committee of the First People’s Hospital of Yunnan Province.

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Zhang, W., Zhang, X., Cheng, P. et al. HSF4 promotes tumor progression of colorectal cancer by transactivating c-MET. Mol Cell Biochem 478, 1141–1150 (2023). https://doi.org/10.1007/s11010-022-04582-2

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  • DOI: https://doi.org/10.1007/s11010-022-04582-2

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