2. Academic Validation
  3. Nuclear receptor coactivator SRC-1 promotes colorectal cancer progression through enhancing GLI2-mediated Hedgehog signaling

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

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. yongyouzhang@xmu.edu.cn.
  • 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. yongyouzhang@xmu.edu.cn.
  • 7 State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China. cdyu@xmu.edu.cn.
  • 8 State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China. mop@xmu.edu.cn.
  • # 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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