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Nuclear receptor coactivator SRC-1 promotes colorectal cancer progression through enhancing GLI2-mediated Hedgehog signaling

Oncogene volume 41, pages 2846–2859 (2022)Cite this article

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Abstract

Overexpression of nuclear coactivator steroid receptor coactivator 1 (SRC-1) and aberrant activation of the Hedgehog (Hh) signaling pathway are associated with various tumorigenesis; however, the significance of SRC-1 in colorectal cancer (CRC) and its contribution to the activation of Hh signaling are unclear. Here, we identified a conserved Hh signaling signature positively correlated with SRC-1 expression in CRC based on TCGA database; SRC-1 deficiency significantly inhibited the proliferation, survival, migration, invasion, and tumorigenesis of both human and mouse CRC cells, and SRC-1 knockout significantly suppressed azoxymethane/dextran sodium sulfate (AOM/DSS)-induced CRC in mice. Mechanistically, SRC-1 promoted the expression of GLI family zinc finger 2 (GLI2), a major downstream transcription factor of Hh pathway, and cooperated with GLI2 to enhance multiple Hh-regulated oncogene expression, including Cyclin D1, Bcl-2, and Slug. Pharmacological blockages of SRC-1 and Hh signaling retarded CRC progression in human CRC cell xenograft mouse model. Together, our studies uncover an SRC-1/GLI2-regulated Hh signaling looping axis that promotes CRC tumorigenesis, offering an attractive strategy for CRC treatment.

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Fig. 1: SRC-1 is overexpressed and positively correlated with GLI2 expression in human CRC specimens.
Fig. 2: SRC-1 promotes the viability, migration, and invasion of CRC cells through enhancing Gli2 expression.
Fig. 3: Knockdown or knockout of SRC-1 inhibits CRC growth and metastasis.
Fig. 4: Knockout of SRC-1 in mice inhibits AOM/DSS-induced CRC tumor growth by downregulating the Hh signaling.
Fig. 5: SRC-1 directly regulates GLI2-associated Hh response gene transcription.
Fig. 6: Pharmacological inhibition of SRC-1 attenuates CRC cell proliferation and tumorigenesis.
Fig. 7: Pharmacological inhibition of SRC-1 enhances the antitumor effect of vismodegib.

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Data availability

TCGA CRC RNA-seq data is available at UCSC XENA website. All other remaining data are included in the article and Supplemental Information files, or available from the authors upon reasonable request.

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Acknowledgements

We would like to thank Shiwen Luo (Nanchang University) for providing GLI2 expression plasmid and Hedgehog signaling reporter 8×GLI. We also thank Dr. Mingxia Zhu for technical support. This work was supported by the National Natural Science Foundation of China (Nos. 81970485 and 81772942 to Chundong Yu, and No. 81772539 to Yongyou Zhang), and the Fundamental Research Funds for the Central Universities (No. 20720180048 to Yongyou Zhang).

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  1. These authors contributed equally: Peng Guo, Qiang Chen, Kesong Peng.

Authors and Affiliations

  1. State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China

    Peng Guo, Qiang Chen, Kesong Peng, Jianyuan Xie, Junjia Liu, Wenjing Ren, Zhangwei Tong, Ming Li, Yongyou Zhang, Chundong Yu & Pingli Mo

  2. Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, 200433, China

    Kesong Peng

  3. National Institute for Data Science in Health and Medicine Engineering, Research Center of Molecular Diagnostics of the Ministry of Education, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China

    Junjia Liu & Yongyou Zhang

  4. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA

    Jianming Xu

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Contributions

PM, CY, and YZ conceived and coordinated the study. PG, QC, KP, YZ, CY, and PM conceived and designed the experiments. PG, QC, KP, JX, JL, WR, ZT, ML, CY, YZ, and PM performed or analyzed the experiments. PG, QC, KP, PM, JXu, CY, and YZ wrote the manuscript.

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Correspondence to Yongyou Zhang, Chundong Yu or Pingli Mo.

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All animal experiments were conducted under protocols approved by the Laboratory Animal Center of Xiamen University. For experiments using human specimens, all specimens were anonymously coded in accordance with the Declaration of Helsinki. The study protocol that conformed to the ethical guidelines was approved by the Medical Ethics Committee at school of medicine, Xiamen University.

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Guo, P., Chen, Q., Peng, K. et al. Nuclear receptor coactivator SRC-1 promotes colorectal cancer progression through enhancing GLI2-mediated Hedgehog signaling. Oncogene 41, 2846–2859 (2022). https://doi.org/10.1038/s41388-022-02308-8

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