2. Academic Validation
  3. Targeting the cholesterol-RORα/γ axis inhibits colorectal cancer progression through degrading c-myc

Targeting the cholesterol-RORα/γ axis inhibits colorectal cancer progression through degrading c-myc

  • Oncogene. 2022 Oct 31. doi: 10.1038/s41388-022-02515-3.
Ying-Nan Wang # 1 2,  Dan-Yun Ruan # 2 3,  Zi-Xian Wang # 1 2,  Kai Yu # 2 4,  Dai-Lin Rong 5,  Ze-Xian Liu 2 4,  Feng Wang 1 2,  Jia-Jia Hu 2 4,  Ying Jin 1 2,  Qi-Nian Wu 2 6,  Heng-Ying Pu 2 4,  Min Wang 2 4,  Rui-Hua Xu 7 8,  Zhao-Lei Zeng 9 10
Affiliations

Affiliations

  • 1 Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, 510060, China.
  • 2 Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, 510060, China.
  • 3 Department of Clinical Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat- Sen University Cancer Center, Guangzhou, China.
  • 4 State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, 510060, China.
  • 5 Department of Radiology, Third Affiliated Hospital of Sun Yat-Sen University, No. 600, Tianhe Road, Guangzhou, Guangdong, 510630, China.
  • 6 Department of Pathology, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, 510060, China.
  • 7 Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, 510060, China. xurh@sysucc.org.cn.
  • 8 Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, 510060, China. xurh@sysucc.org.cn.
  • 9 Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, 510060, China. zengzhl@sysucc.org.cn.
  • 10 State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, 510060, China. zengzhl@sysucc.org.cn.
  • # Contributed equally.
PMID: 36316442 DOI: 10.1038/s41388-022-02515-3
Abstract

Dysregulated Cholesterol metabolism is a hallmark of colorectal Cancer (CRC). However, the usage of cholesterol-lowering agents seemed to have no benefit in CRC patients. In this study, we focused on the cholesterol-nuclear receptors (NRs) axis as a strategy. Cholesterol and its derivatives work as ligands for different nuclear receptors, thus promoting Cancer progression. The key NR downstream of Cholesterol in CRC is unknown. Here, we treated CRC cells with a cholesterol-lowering agent and lipoprotein-depleted conditioned medium, and then detected the change of the putative NRs. The results revealed that RORα/γ (Retinoic acid receptor-related Orphan Receptor α/γ) levels exhibited the most obvious increases in CRC cells subjected them to Cholesterol deprivation. RORα/γ agonists significantly inhibited CRC cells proliferation and migration in vitro and in vivo. Also, RORα/γ overexpression repressed CRC cells proliferation and migration in vitro and in vivo and RORα/γ knockdown promoted it. Mechanistically, RORα/γ agonists promoted c-Myc degradation by activating the transcription of the ubiquitinase NEDD4. Intriguingly, the combination of RORα/γ agonists and atorvastatin had a synergistic effect on inhibiting CRC cells. These findings demonstrate that the cholesterol- RORα/γ axis is important for maintaining c-Myc protein levels. Combination therapy with atorvastatin and RORα/γ agonist is a promising therapeutic strategy for CRC.

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