miR-137 targets p160 steroid receptor coactivators SRC1, SRC2, and SRC3 and inhibits cell proliferation

Vijay Kumar Eedunuri, Kimal Rajapakshe, Warren Fiskus, Chuandong Geng, Sue Anne Chew, Christopher Foley, Shrijal S. Shah, John Shou, Junaith Mohamed, Cristian Coarfa, Bert W. O’Malley, Nicholas Mitsiades

Research output: Contribution to journalArticle

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Abstract

The p160 family of steroid receptor coactivators (SRCs) are pleiotropic transcription factor coactivators and “master regulators” of gene expression that promote cancer cell proliferation, survival, metabolism, migration, invasion, and metastasis. Cancers with high p160 SRC expression exhibit poor clinical outcomes and resistance to therapy, highlighting the SRCs as critical oncogenic drivers and, thus, therapeutic targets. microRNAs are important epigenetic regulators of protein expression. To examine the regulation of p160 SRCs by microRNAs, we used and combined 4 prediction algorithms to identify microRNAs that could target SRC1, SRC2, and SRC3 expression. For validation of these predictions, we assessed p160 SRC protein expression and cell viability after transfection of corresponding microRNA mimetics in breast cancer, uveal melanoma, and prostate cancer (PC) cell lines. Transfection of selected microRNA mimetics into breast cancer, uveal melanoma, and PC cells depleted SRC protein expression levels and exerted potent antiproliferative activity in these cell types. In particular, microRNA-137 (miR-137) depleted expression of SRC1, SRC2, and very potently, SRC3. The latter effect can be attributed to the presence of 3 miR-137 recognition sequences within the SRC3 3-untranslated region. Using reverse phase protein array analysis, we identified a network of proteins, in addition to SRC3, that were modulated by miR-137 in PC cells. We also found that miR-137 and its host gene are epigenetically silenced in human cancer specimens and cell lines. These results support the development and testing of microRNA-based therapies (in particular based on restoring miR-137 levels) for targeting the oncogenic family of p160 SRCs in cancer.

Original languageEnglish (US)
Pages (from-to)1170-1183
Number of pages14
JournalMolecular Endocrinology
Volume29
Issue number8
DOIs
StatePublished - Jul 31 2015
Externally publishedYes

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Nuclear Receptor Coactivator 2
MicroRNAs
Cell Proliferation
Steroid Receptors
Prostatic Neoplasms
Transfection
Neoplasms
Cell Survival
Proteins
Breast Neoplasms
Cell Line
Protein Array Analysis
3' Untranslated Regions
Regulator Genes
Epigenomics

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Endocrinology

Cite this

Eedunuri, V. K., Rajapakshe, K., Fiskus, W., Geng, C., Chew, S. A., Foley, C., ... Mitsiades, N. (2015). miR-137 targets p160 steroid receptor coactivators SRC1, SRC2, and SRC3 and inhibits cell proliferation. Molecular Endocrinology, 29(8), 1170-1183. https://doi.org/10.1210/me.2015-1080

miR-137 targets p160 steroid receptor coactivators SRC1, SRC2, and SRC3 and inhibits cell proliferation. / Eedunuri, Vijay Kumar; Rajapakshe, Kimal; Fiskus, Warren; Geng, Chuandong; Chew, Sue Anne; Foley, Christopher; Shah, Shrijal S.; Shou, John; Mohamed, Junaith; Coarfa, Cristian; O’Malley, Bert W.; Mitsiades, Nicholas.

In: Molecular Endocrinology, Vol. 29, No. 8, 31.07.2015, p. 1170-1183.

Research output: Contribution to journalArticle

Eedunuri, VK, Rajapakshe, K, Fiskus, W, Geng, C, Chew, SA, Foley, C, Shah, SS, Shou, J, Mohamed, J, Coarfa, C, O’Malley, BW & Mitsiades, N 2015, 'miR-137 targets p160 steroid receptor coactivators SRC1, SRC2, and SRC3 and inhibits cell proliferation', Molecular Endocrinology, vol. 29, no. 8, pp. 1170-1183. https://doi.org/10.1210/me.2015-1080
Eedunuri, Vijay Kumar ; Rajapakshe, Kimal ; Fiskus, Warren ; Geng, Chuandong ; Chew, Sue Anne ; Foley, Christopher ; Shah, Shrijal S. ; Shou, John ; Mohamed, Junaith ; Coarfa, Cristian ; O’Malley, Bert W. ; Mitsiades, Nicholas. / miR-137 targets p160 steroid receptor coactivators SRC1, SRC2, and SRC3 and inhibits cell proliferation. In: Molecular Endocrinology. 2015 ; Vol. 29, No. 8. pp. 1170-1183.
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abstract = "The p160 family of steroid receptor coactivators (SRCs) are pleiotropic transcription factor coactivators and “master regulators” of gene expression that promote cancer cell proliferation, survival, metabolism, migration, invasion, and metastasis. Cancers with high p160 SRC expression exhibit poor clinical outcomes and resistance to therapy, highlighting the SRCs as critical oncogenic drivers and, thus, therapeutic targets. microRNAs are important epigenetic regulators of protein expression. To examine the regulation of p160 SRCs by microRNAs, we used and combined 4 prediction algorithms to identify microRNAs that could target SRC1, SRC2, and SRC3 expression. For validation of these predictions, we assessed p160 SRC protein expression and cell viability after transfection of corresponding microRNA mimetics in breast cancer, uveal melanoma, and prostate cancer (PC) cell lines. Transfection of selected microRNA mimetics into breast cancer, uveal melanoma, and PC cells depleted SRC protein expression levels and exerted potent antiproliferative activity in these cell types. In particular, microRNA-137 (miR-137) depleted expression of SRC1, SRC2, and very potently, SRC3. The latter effect can be attributed to the presence of 3 miR-137 recognition sequences within the SRC3 3-untranslated region. Using reverse phase protein array analysis, we identified a network of proteins, in addition to SRC3, that were modulated by miR-137 in PC cells. We also found that miR-137 and its host gene are epigenetically silenced in human cancer specimens and cell lines. These results support the development and testing of microRNA-based therapies (in particular based on restoring miR-137 levels) for targeting the oncogenic family of p160 SRCs in cancer.",
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AU - Chew, Sue Anne

AU - Foley, Christopher

AU - Shah, Shrijal S.

AU - Shou, John

AU - Mohamed, Junaith

AU - Coarfa, Cristian

AU - O’Malley, Bert W.

AU - Mitsiades, Nicholas

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