Abstract | BACKGROUND: METHODS:
Hypoxia-responsive circular RNAs ( circRNAs) were identified by high throughput RNA sequencing between CRC cells cultured under normoxia or hypoxia. The protein-coding potential of circINSIG1 was identified by polysome profiling and LC-MS. The function of circINSIG1 was validated in vitro and in vivo by gain or loss of function assays. Mechanistic results were concluded by immunoprecipitation analyses. RESULTS: A novel hypoxia-responsive circRNA named circINSIG1 was identified, which was upregulated in CRC tissues and correlated with advanced clinical stages and poor survival. Mechanistically, circINSIG1 encoded a 121 amino acid protein circINSIG1-121 to promote K48-linked ubiquitination of the critical cholesterol metabolism regulator INSIG1 at lysine 156 and 158 by recruiting CUL5-ASB6 complex, a ubiquitin E3 ligase complex, thereby inducing cholesterol biosynthesis to promote CRC proliferation and metastasis. The orthotopic xenograft tumor models and patient-derived xenograft models further identified the role of circINSIG1 in CRC progression and potential therapeutic target of CRC. CONCLUSIONS: circINSIG1 presents an epigenetic mechanism which provides insights into the crosstalk between hypoxia and cholesterol metabolism, and provides a promising therapeutic target for the treatment of CRC.
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Authors | Li Xiong, Hua-Shan Liu, Chi Zhou, Xin Yang, Liang Huang, Hai-Qing Jie, Zi-Wei Zeng, Xiao-Bin Zheng, Wen-Xin Li, Zhan-Zhen Liu, Liang Kang, Zhen-Xing Liang |
Journal | Molecular cancer
(Mol Cancer)
Vol. 22
Issue 1
Pg. 72
(04 22 2023)
ISSN: 1476-4598 [Electronic] England |
PMID | 37087475
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | © 2023. The Author(s). |
Chemical References |
- Cholesterol
- CUL5 protein, human
- Cullin Proteins
- INSIG1 protein, human
- Intracellular Signaling Peptides and Proteins
- Membrane Proteins
- RNA, Circular
- Ubiquitin
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Topics |
- Humans
- Cell Proliferation
- Cholesterol
(metabolism)
- Colorectal Neoplasms
(genetics, metabolism)
- Cullin Proteins
(genetics)
- Epigenesis, Genetic
- Gene Expression Regulation, Neoplastic
- Hypoxia
(genetics)
- Intracellular Signaling Peptides and Proteins
(genetics, metabolism)
- Membrane Proteins
(genetics, metabolism)
- RNA, Circular
(genetics, metabolism)
- Ubiquitin
(metabolism)
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