CCT3-LINC00326 axis regulates hepatocarcinogenic lipid metabolism
Jonas Nørskov Søndergaard1, Christian Sommerauer1, Ionut Atanasoai1
1Department of Microbiology, Tumor, and Cell Biology, Science for Life Laboratory, Karolinska Institute, Stockholm, Sweden.
Objective:
To better comprehend transcriptional phenotypes of cancer cells, we globally characterised RNA-binding proteins (RBPs) to identify altered RNAs, including long non-coding RNAs (lncRNAs).
Design:
To unravel RBP-lncRNA interactions in cancer, we curated a list of ~2300 highly expressed RBPs in human cells, tested effects of RBPs and lncRNAs on patient survival in multiple cohorts, altered expression levels, integrated various sequencing, molecular and cell-based data.
Results:
High expression of RBPs negatively affected patient survival in 21 cancer types, especially hepatocellular carcinoma (HCC). After knockdown of the top 10 upregulated RBPs and subsequent transcriptome analysis, we identified 88 differentially expressed lncRNAs, including 34 novel transcripts. CRISPRa-mediated overexpression of four lncRNAs had major effects on the HCC cell phenotype and transcriptome. Further investigation of four RBP-lncRNA pairs revealed involvement in distinct regulatory processes. The most noticeable RBP-lncRNA connection affected lipid metabolism, whereby the non-canonical RBP CCT3 regulated LINC00326 in a chaperonin-independent manner. Perturbation of the CCT3-LINC00326 regulatory network led to decreased lipid accumulation and increased lipid degradation in cellulo as well as diminished tumour growth in vivo.
Conclusions:
We revealed that RBP gene expression is perturbed in HCC and identified that RBPs exerted additional functions beyond their tasks under normal physiological conditions, which can be stimulated or intensified via lncRNAs and affected tumour growth.
Insights
Altered RNA-binding proteins (RBPs) and long non-coding RNAs (lncRNAs) impact cancer patient survival. A specific RBP-lncRNA pair, CCT3-LINC00326, regulates lipid metabolism and inhibits hepatocellular carcinoma tumor growth.
Area of Science:
- Molecular Biology
- Cancer Research
- Genomics
Background:
- RNA-binding proteins (RBPs) play crucial roles in gene regulation.
- Long non-coding RNAs (lncRNAs) are increasingly recognized for their involvement in cancer.
- Understanding RBP-lncRNA interactions is vital for comprehending cancer biology.
Purpose of the Study:
- To globally characterize RNA-binding proteins (RBPs) and their associated altered RNAs, including lncRNAs, in cancer.
- To investigate the functional impact of RBP-lncRNA interactions on cancer phenotypes and patient survival.
Main Methods:
- Curated a list of ~2300 highly expressed RBPs in human cells.
- Analyzed RBP and lncRNA effects on patient survival across multiple cancer cohorts.
- Integrated diverse sequencing, molecular, and cell-based data.
- Performed RBP knockdown and lncRNA overexpression studies in hepatocellular carcinoma (HCC) models.
Main Results:
- High RBP expression correlated with reduced patient survival in 21 cancer types, notably HCC.
- Identified 88 differentially expressed lncRNAs, including 34 novel transcripts, after RBP knockdown.
- Overexpression of four lncRNAs significantly altered HCC cell phenotype and transcriptome.
- Discovered a novel regulatory network involving RBP CCT3 and lncRNA LINC00326 in lipid metabolism, which suppressed HCC tumor growth in vivo.
Conclusions:
- RBP gene expression is perturbed in HCC, with RBPs exhibiting functions beyond normal physiological roles.
- RBPs, modulated by lncRNAs, can significantly impact cancer progression and tumor growth.
- The CCT3-LINC00326 axis represents a potential therapeutic target for HCC by modulating lipid metabolism.
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