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Long Noncoding RNA EPCART Regulates Translation Through PI3K/AKT/mTOR Pathway and PDCD4 in Prostate Cancer - Beyond the Abstract

Prostate cancer continues to be a leading cause of cancer-related mortality among men, with dysregulation of signaling pathways such as PI3K/AKT/mTOR serving as a characteristic feature of its progression.1

While much research has been focused on protein-coding genes, long noncoding RNAs (lncRNAs) have increasingly garnered interest for their regulatory roles in cancer biology. In prostate cancer, for example, the expression of multiple lncRNAs is aberrated in primary tumors and metastases.2,3 In this study, we explored the emerging role of lncRNA EPCART in prostate cancer, particularly its impact on the regulation of translation through key cancer-related pathways.4

Previous studies have identified elevated levels of EPCART expression in prostate cancer tissues as being associated with adverse clinical outcomes,2,5 suggesting that EPCART may contribute to the aggressive nature of advanced prostate cancer. Our earlier knockout studies of EPCART in prostate cancer cells also indicated its potential oncogenic role in prostate cancer.2

To elucidate the molecular mechanisms underlying EPCART function, we conducted RNA sequencing and quantitative mass spectrometry on EPCART-knockout cells, examining the pathways and target proteins affected by its silencing.4 We discovered that EPCART modulates the translational machinery of PCa cells. Further validation demonstrated that EPCART functions as a modulator of the PI3K/AKT/mTOR pathway, which is integral to key cellular processes such as protein synthesis and cell survival.6 Specifically, EPCART impacts the degradation of the tumor suppressor PDCD4, thereby influencing translational control. PDCD4 normally inhibits protein synthesis by repressing eukaryotic initiation factors involved in translation.7 However, EPCART appears to counteract this function, potentially promoting dysregulated protein synthesis—a key driver of tumor growth.

The reduction of PDCD4 expression is commonly associated with poor outcomes and increased cancer aggressiveness.8 By immunohistochemical analysis of PDCD4 expression in prostate cancer tissues we revealed that there is a significant decrease in PDCD4 levels in more aggressive tumors compared to primary prostate cancer tissues. Moreover, EPCART expression was found to negatively correlate with PDCD4 protein levels, further supporting the link between EPCART and PDCD4 in prostate cancer tissues. These observations support the established role of PDCD4 as a tumor suppressor and further reinforce that dysregulated expression of both PDCD4 and EPCART correlates with poorer clinical outcomes in prostate cancer.

The findings of this study offer significant insights into the role of lncRNAs in cancer biology, specifically in the context of translational control.4 The identification of EPCART as a regulator of the PI3K/AKT/mTOR signaling pathway opens new avenues for therapeutic strategies targeting lncRNAs in cancer. Future research could focus on further characterizing the molecular interactions of EPCART, exploring its potential as a therapeutic target, and developing interventions aimed at disrupting its oncogenic functions. Overall, this study contributes to the growing body of literature on the role of noncoding RNAs in cancer and highlights the therapeutic potential of targeting these molecules in the treatment of prostate cancer and other malignancies.

Written by: Annika Kohvakka,1 Tapio Visakorpi1 and Leena Latonen2

  1. Prostate Cancer Research Center, Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Center, Tampere University Hospital, Tampere, Finland.
  2. Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
References:

  1. Shorning BY, Dass MS, Smalley MJ, Pearson HB. The PI3K-AKT-mTOR Pathway and Prostate Cancer: At the Crossroads of AR, MAPK, and WNT Signaling. Int J Mol Sci. 2020 Jun 25;21(12):4507.
  2. Kohvakka A, Sattari M, Shcherban A, Annala M, Urbanucci A, Kesseli J, et al. AR and ERG drive the expression of prostate cancer-specific long noncoding RNAs. Oncogene. 2020 Jul;39(30):5241–51. doi: 10.1038/s41388-020-1365-6.
  3. Sattari M, Kohvakka A, Moradi E, Rauhala H, Urhonen H, Isaacs WB, Nykter M, Murtola TJ, Tammela TLJ, Latonen L, Bova GS, Kesseli J, Visakorpi T. Identification of long noncoding RNAs with aberrant expression in prostate cancer metastases. Endocr Relat Cancer. 2023 Jun 26;30(8):e220247. doi: 10.1530/ERC-22-0247
  4. Kohvakka A, Sattari M, Nättinen J, Aapola U, Gregorová P, Tammela TLJ, Uusitalo H, Sarin LP, Visakorpi T, Latonen L. Long noncoding RNA EPCART regulates translation through PI3K/AKT/mTOR pathway and PDCD4 in prostate cancer. Cancer Gene Ther. 2024 Aug 15. doi: 10.1038/s41417-024-00822-3.
  5. Böttcher R, Hoogland AM, Dits N, Verhoef EI, Kweldam C, Waranecki P, et al. Novel long non-coding RNAs are specific diagnostic and prognostic markers for prostate cancer. Oncotarget. 2015 Feb 28;6(6):4036–50.
  6. Roux PP, Topisirovic I. Signaling Pathways Involved in the Regulation of mRNA Translation. Mol Cell Biol. 2018 Jun 1;38(12):e00070-18.
  7. Suzuki C, Garces RG, Edmonds KA, Hiller S, Hyberts SG, Marintchev A, et al. PDCD4 inhibits translation initiation by binding to eIF4A using both its MA3 domains. Proc Natl Acad Sci U S A. 2008 Mar 4;105(9):3274–9.
  8. Li JZH, Gao W, Ho WK, Lei WB, Wei WI, Chan JYW, et al. The clinical association of programmed cell death protein 4 (PDCD4) with solid tumors and its prognostic significance: a meta-analysis. Chin J Cancer. 2016 Nov 16;35(1):95.
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