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

  • Oncogene. 2022 May;41(20):2846-2859. doi: 10.1038/s41388-022-02308-8.
Peng Guo   #  1 ,  Qiang Chen   #  1 ,  Kesong Peng   #  1  2 ,  Jianyuan Xie  1 ,  Junjia Liu  1  3 ,  Wenjing Ren  1 ,  Zhangwei Tong  1 ,  Ming Li  1 ,  Jianming Xu  4 ,  Yongyou Zhang  5  6 ,  Chundong Yu  7 ,  Pingli Mo  8
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.
  • 2. Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, 200433, China.
  • 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.
  • 4. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
  • 5. State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China. [email protected].
  • 6. 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. [email protected].
  • 7. State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China. [email protected].
  • 8. State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China. [email protected].
  • # Contributed equally.
PMID: 35418691 DOI: 10.1038/s41388-022-02308-8
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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