Loss of androgen-regulated MicroRNA 1 activates SRC and promotes prostate cancer bone metastasis

Yen Nien Liu, JuanJuan Yin, Ben Barrett, Heather Sheppard-Tillman, Dongmei Li, Orla M. Casey, Lei Fang, Paul G. Hynes, Amir H. Ameri, Kathleen Kelly

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30 Citations (Scopus)

Abstract

Bone metastasis is the hallmark of progressive and castration-resistant prostate cancers. MicroRNA 1 (miR-1) levels are decreased in clinical samples of primary prostate cancer and further reduced in metastases. SRC has been implicated as a critical factor in bone metastasis, and here we show that SRC is a direct target of miR-1. In prostate cancer patient samples, miR-1 levels are inversely correlated with SRC expression and a SRC-dependent gene signature. Ectopic miR-1 expression inhibited extracellular signal-regulated kinase (ERK) signaling and bone metastasis in a xenograft model. In contrast, SRC overexpression was sufficient to reconstitute bone metastasis and ERK signaling in cells expressing high levels of miR-1. Androgen receptor (AR) activity, defined by an AR output signature, is low in a portion of castration-resistant prostate cancer. We show that AR binds to the miR-1-2 regulatory region and regulates miR-1 transcription. Patients with low miR-1 levels displayed correlated low canonical AR gene signatures. Our data support the existence of an AR-miR-1-SRC regulatory network. We propose that loss of miR-1 is one mechanistic link between low canonical AR output and SRC-promoted metastatic phenotypes.

Original languageEnglish
Pages (from-to)1940-1951
Number of pages12
JournalMolecular and Cellular Biology
Volume35
Issue number11
DOIs
Publication statusPublished - 2015

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ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Liu, Y. N., Yin, J., Barrett, B., Sheppard-Tillman, H., Li, D., Casey, O. M., Fang, L., Hynes, P. G., Ameri, A. H., & Kelly, K. (2015). Loss of androgen-regulated MicroRNA 1 activates SRC and promotes prostate cancer bone metastasis. Molecular and Cellular Biology, 35(11), 1940-1951. https://doi.org/10.1128/MCB.00008-15