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LncRNA CRCMSL interferes in phospholipid unsaturation to suppress colorectal cancer progression via reducing membrane
Muhong Jiang1, Lijun Xu1, Wandie Lin2
1Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Department of Pathology & Guangdong Province Key Laboratory of Molecular Tumor Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China; Department of Pathology, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), Foshan, China.
Introduction:
Reprogrammed metabolism is an important basis of colorectal cancer (CRC) progression; however, its mechanisms remain unclear. This study illustrated a novel mechanism for long noncoding RNA (lncRNA) CRCMSL in CRC, which was identified as a CRC suppressor in our previous study.
Objective:
To investigate whether CRCMSL suppresses colorectal cancer by interfering in lipid metabolism.
Methods:
Potential functions of CRCMSL were predicted by GSEA, which led to lipidomics. Ferroptosis process in CRC were evaluated by protein markers, probe-reported lipid peroxidation signals and transmission electron microscopy. Order and fluidity of phospholipid bilayers were detected by Laurdan generalized polarization (GP) assays and fluorescence recovery after photobleaching (FRAP) assays, respectively. RNA pull-down and RIP assays were performed to explore the target of CRCMSL. qPCR, western blot and enzyme activity detections were used to explore the effects of CRCMSL on the target. Orthotopic and subcutaneous xenografts in nude mice were used to validate efficacy of CRC in vivo.
Results:
CRCMSL-knockdown upregulated lipid synthesis and remodeled fatty acyl chains in phospholipids, inspiring studies on ferroptosis and phospholipid bilayers. CRCMSL-mediated biological processes and behaviors were restored by stearoyl-CoA desaturase (SCD), a key enzyme for the synthesis of monounsaturated fatty acids (MUFAs), suggesting that CRCMSL promotes ferroptosis and reduces membrane fluidity by interfering in phospholipid unsaturation. The target of CRCMSL in fatty acid metabolism is acetyl-CoA carboxylase 1 (ACC1), a key enzyme for de novo fatty acid synthesis. CRCMSL promoted ACC1 phosphorylation to restrict its activity. Firsocostat, an ACC oral inhibitor ND630, is a potential drug for CRC treatment in combination with CRCMSL.
Conclusion:
Our study illustrated a novel mechanism of CRCMSL-ACC1 axis-associated fatty acid metabolism in CRC progression, providing laboratory evidence for the development of targeted therapies for patients with advanced CRC.
Insights
The long noncoding RNA CRCMSL suppresses colorectal cancer by regulating fatty acid metabolism and promoting ferroptosis. This discovery offers new therapeutic targets for advanced colorectal cancer (CRC).
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Reprogrammed metabolism drives colorectal cancer (CRC) progression, but underlying mechanisms are not fully understood.
- The long noncoding RNA (lncRNA) CRCMSL was previously identified as a suppressor of CRC.
Purpose of the Study:
- To investigate if CRCMSL suppresses colorectal cancer by influencing lipid metabolism.
- To elucidate the molecular mechanisms by which CRCMSL affects CRC progression.
Main Methods:
- Gene Set Enrichment Analysis (GSEA) and lipidomics were employed to predict and analyze metabolic functions.
- Ferroptosis was assessed using protein markers, lipid peroxidation signals, and electron microscopy.
- Phospholipid bilayer properties were evaluated using Laurdan GP and FRAP assays.
- RNA pull-down, RIP, qPCR, and Western blot assays identified and validated CRCMSL's target, acetyl-CoA carboxylase 1 (ACC1).
- In vivo efficacy was tested using orthotopic and subcutaneous xenografts in nude mice.
Main Results:
- CRCMSL knockdown increased lipid synthesis and altered fatty acyl chains, impacting ferroptosis and phospholipid bilayers.
- CRCMSL promotes ferroptosis and reduces membrane fluidity by interfering with phospholipid unsaturation, a process mediated by stearoyl-CoA desaturase (SCD).
- CRCMSL targets acetyl-CoA carboxylase 1 (ACC1), inhibiting its activity through phosphorylation.
- The ACC inhibitor Firsocostat (ND630) shows potential for CRC treatment in combination with CRCMSL.
Conclusions:
- A novel mechanism involving the CRCMSL-ACC1 axis in fatty acid metabolism was elucidated for CRC progression.
- This study provides a basis for developing targeted therapies for advanced colorectal cancer.
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