AR and ERG drive the expression of prostate cancer specific long noncoding RNAs

Abstract

Long noncoding RNAs (lncRNAs) play pivotal roles in cancer development and progression, and some function in a highly cancer-specific manner. However, whether the cause of their expression is an outcome of a specific regulatory mechanism or nonspecific transcription induced by genome reorganization in cancer remains largely unknown. Here, we investigated a group of lncRNAs that we previously identified to be aberrantly expressed in prostate cancer (PC), called TPCATs. Our high-throughput real-time PCR experiments were integrated with publicly available RNA-seq and ChIP-seq data and revealed that the expression of a subset of TPCATs is driven by PC-specific transcription factors (TFs), especially androgen receptor (AR) and ETS-related gene (ERG). Our in vitro validations confirmed that AR and ERG regulated a subset of TPCATs, most notably for EPCART. Knockout of EPCART was found to reduce migration and proliferation of the PC cells in vitro. The high expression of EPCART and two other TPCATs (TPCAT-3-174133 and TPCAT-18-31849) were also associated with the biochemical recurrence of PC in prostatectomy patients and were independent prognostic markers. Our findings suggest that the expression of numerous PC-associated lncRNAs is driven by PC-specific mechanisms and not by random cellular events that occur during cancer development. Furthermore, we report three prospective prognostic markers for the early detection of advanced PC and show EPCART to be a functionally relevant lncRNA in PC.

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Fig. 1: ERG overexpression correlates with the expression of TPCATs.
Fig. 2: Several TPCATs are regulated by AR and ERG.
Fig. 3: TFs that drive PC colocalize in the regulatory regions of TPCATs.
Fig. 4: EPCART is an androgen responsive lncRNA that associates with PC progression.

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Acknowledgements

This study was supported by grants from the Academy of Finland (TV 317755, MN 310829, and LL 317871), Sigrid Juselius Foundation (TV and LL), Cancer Society of Finland, Business Finland, the Finnish Cultural Foundation (AK), the European Union’s Horizon 2020 (MS, TransPot - 721746), Norwegian Cancer Society grant (AU 198016-2018), Research collegium of the University of Tampere/IASR (KK). The authors want to thank Jenni Jouppila, Paula Kosonen, Riina Kylätie, Päivi Martikainen, Hanna Selin, and Marika Vähä-Jaakkola for their technical assistance and Tampere Imaging Facility (TIF) for their service. The results published here are in part based upon data generated by The Cancer Genome Atlas project (dbGaP Study Accession: phs000178.v9.p8) established by the NCI and NHGRI. Information about TCGA can be found at http://cancergenome.nih.gov. We acknowledge ENCODE Consortium and the ENCODE production laboratories for generating the DNase-seq data.

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Correspondence to Tapio Visakorpi.

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Kohvakka, A., Sattari, M., Shcherban, A. et al. AR and ERG drive the expression of prostate cancer specific long noncoding RNAs. Oncogene 39, 5241–5251 (2020). https://doi.org/10.1038/s41388-020-1365-6

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