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MiR-221 promotes the development of androgen independence in prostate cancer cells via downregulation of HECTD2 and RAB1A

Oncogene volume 33, pages 2790–2800 (2014)Cite this article

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Abstract

Hormone-sensitive prostate cancer typically progresses to castration resistant prostate cancer (CRPC) after the androgen deprivation therapy. We investigated the impact of microRNAs (miRs) in the transition of prostate cancer to CRPC. MiR-221/-222 was highly expressed in bone metastatic CRPC tumor specimens. We previously demonstrated that transient overexpression of miR-221/-222 in LNCaP promoted the development of the CRPC phenotype. In current study, we show that stably overexpressing miR-221 confers androgen independent (AI) cell growth in LNCaP by rescuing LNCaP cells from growth arrest at G1 phase due to the lack of androgen. Overexpressing of miR-221 in LNCaP reduced the transcription of a subgroup of androgen-responsive genes without affecting the androgen receptor (AR) or AR-androgen integrity. By performing systematic biochemical and bioinformatical analyses, we identified two miR-221 targets, HECTD2 and RAB1A, which could mediate the development of CRPC phenotype in multiple prostate cancer cell lines. Downregulation of HECTD2 significantly affected the androgen-induced and AR-mediated transcription, and downregulation of HECTD2 or RAB1A enhances AI cell growth. As a result of the elevated expression of miR-221, expression of many cell cycle genes was altered and pathways promoting epithelial to mesenchymal transition/tumor metastasis were activated. We hypothesize that a major biological consequence of upregulation of miR-221 is reprogramming of AR signaling, which in turn may mediate the transition to the CRPC phenotype.

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Acknowledgements

This work was supported by a SPORE in Prostate Cancer 2 P50 CA090381-06 and TS was supported by a Department of Defense (DoD) Prostate Cancer Training Award W81XWH-09-1-0372. We thank Dr Peter T Nelson at University of Kentucky and Dr Zissimos Mourelatos at University of Pennsylvania for kindly providing us the anti-AGO antibody. We also thank Dr Wang-xia Wang for technical suggestions on AGO-RIP-Chip experiments.

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Authors and Affiliations

  1. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

    T Sun, X Wang, H H He, C J Sweeney, M Brown, G-SM Lee & P W Kantoff

  2. Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

    H H He & S X Liu

  3. Department of Medicine, Cancer Biology Program, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    S Balk

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Sun, T., Wang, X., He, H. et al. MiR-221 promotes the development of androgen independence in prostate cancer cells via downregulation of HECTD2 and RAB1A. Oncogene 33, 2790–2800 (2014). https://doi.org/10.1038/onc.2013.230

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