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Sequencing Small Non-coding RNA from Formalin-fixed Tissues and Serum-derived Exosomes from Castration-resistant Prostate Cancer Patients
Published on: November 19, 2019
Long noncoding RNA EPCART regulates translation through PI3K/AKT/mTOR pathway and PDCD4 in prostate cancer
Annika Kohvakka1, Mina Sattari1, Janika Nättinen2
1Prostate Cancer Research Center, Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Center, Tampere University Hospital, 33520, Tampere, Finland.
Abstract:
While hundreds of cancer-associated long noncoding RNAs (lncRNAs) have been discovered, their functional role in cancer cells is still largely a mystery. An increasing number of lncRNAs are recognized to function in the cytoplasm, e.g., as modulators of translation. Here, we investigated the detailed molecular identity and functional role of EPCART, a lncRNA we previously discovered to be a potential oncogene in prostate cancer (PCa). First, we interrogated the transcript structure of EPCART and then confirmed EPCART to be a non-peptide-coding lncRNA using in silico methods. Pathway analysis of differentially expressed protein-coding genes in EPCART knockout cells implied that EPCART modulates the translational machinery of PCa cells. EPCART was also largely located in the cytoplasm and at the sites of translation. With quantitative proteome analysis on EPCART knockout cells we discovered PDCD4, an inhibitor of protein translation, to be increased by EPCART reduction. Further studies indicated that the inhibitory effect of EPCART silencing on translation was mediated by reduced activation of AKT and inhibition of the mTORC1 pathway. Together, our findings identify EPCART as a translation-associated lncRNA that functions via modulation of the PI3K/AKT/mTORC1 pathway in PCa cells. Furthermore, we provide evidence for the prognostic potential of PDCD4 in PCa tumors in connection with EPCART.
Insights
This study reveals EPCART, a long noncoding RNA (lncRNA), regulates protein translation in prostate cancer (PCa) by influencing the PI3K/AKT/mTORC1 pathway. Reduced EPCART increases PDCD4, impacting PCa progression.
Area of Science:
- Molecular Biology
- Oncology
- Genetics
Background:
- Long noncoding RNAs (lncRNAs) are increasingly recognized for their roles in cancer, with many functioning in the cytoplasm to modulate translation.
- The specific functions of numerous cancer-associated lncRNAs remain largely uncharacterized.
- Prostate cancer (PCa) presents a significant clinical challenge, necessitating a deeper understanding of its molecular underpinnings.
Purpose of the Study:
- To elucidate the molecular identity and functional role of EPCART, a previously identified potential oncogene in prostate cancer.
- To investigate how EPCART influences the translational machinery within prostate cancer cells.
- To explore the therapeutic and prognostic potential of EPCART and its associated pathways.
Main Methods:
- In silico analysis to determine the transcript structure and confirm EPCART as a non-peptide-coding lncRNA.
- Pathway analysis of differentially expressed genes in EPCART knockout cells.
- Quantitative proteome analysis to identify protein changes upon EPCART modulation.
- Investigation of signaling pathways, including PI3K/AKT/mTORC1, following EPCART manipulation.
Main Results:
- EPCART was confirmed as a non-peptide-coding lncRNA primarily localized in the cytoplasm at translation sites.
- EPCART knockout cells exhibited altered translational machinery, with increased levels of PDCD4, a translation inhibitor.
- EPCART silencing led to reduced AKT activation and mTORC1 pathway inhibition, impacting overall protein translation.
- PDCD4 was identified as a key mediator in EPCART's translational control.
Conclusions:
- EPCART functions as a translation-associated lncRNA in prostate cancer cells.
- EPCART modulates protein translation through the PI3K/AKT/mTORC1 signaling pathway.
- EPCART and PDCD4 hold potential as prognostic biomarkers in prostate cancer.
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