title: miR-137 Targets p160 Steroid Receptor Coactivators SRC1, SRC2, and SRC3 and Inhibits Cell Proliferation.
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.
authors.affiliation: Adrienne Helis Malvin Medical Research Foundation (V.K.E.), New Orleans, Louisiana 70130; and Departments of Molecular and Cellular Biology (K.R., W.F., C.G., S.A.C., C.F., S.S.S., J.S., J.S.M., C.C., B.W.O., N.M.) and Department of Medicine (W.F., C.G., S.A.C., C.F., S.S.S., J.S., J.S.M., N.M.), Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Vijay Kumar
authors.initials: VK
authors.lastname: Eedunuri
authors.affiliation: Adrienne Helis Malvin Medical Research Foundation (V.K.E.), New Orleans, Louisiana 70130; and Departments of Molecular and Cellular Biology (K.R., W.F., C.G., S.A.C., C.F., S.S.S., J.S., J.S.M., C.C., B.W.O., N.M.) and Department of Medicine (W.F., C.G., S.A.C., C.F., S.S.S., J.S., J.S.M., N.M.), Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Kimal
authors.initials: K
authors.lastname: Rajapakshe
authors.affiliation: Adrienne Helis Malvin Medical Research Foundation (V.K.E.), New Orleans, Louisiana 70130; and Departments of Molecular and Cellular Biology (K.R., W.F., C.G., S.A.C., C.F., S.S.S., J.S., J.S.M., C.C., B.W.O., N.M.) and Department of Medicine (W.F., C.G., S.A.C., C.F., S.S.S., J.S., J.S.M., N.M.), Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Warren
authors.initials: W
authors.lastname: Fiskus
authors.affiliation: Adrienne Helis Malvin Medical Research Foundation (V.K.E.), New Orleans, Louisiana 70130; and Departments of Molecular and Cellular Biology (K.R., W.F., C.G., S.A.C., C.F., S.S.S., J.S., J.S.M., C.C., B.W.O., N.M.) and Department of Medicine (W.F., C.G., S.A.C., C.F., S.S.S., J.S., J.S.M., N.M.), Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Chuandong
authors.initials: C
authors.lastname: Geng
authors.affiliation: Adrienne Helis Malvin Medical Research Foundation (V.K.E.), New Orleans, Louisiana 70130; and Departments of Molecular and Cellular Biology (K.R., W.F., C.G., S.A.C., C.F., S.S.S., J.S., J.S.M., C.C., B.W.O., N.M.) and Department of Medicine (W.F., C.G., S.A.C., C.F., S.S.S., J.S., J.S.M., N.M.), Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Sue Anne
authors.initials: SA
authors.lastname: Chew
authors.affiliation: Adrienne Helis Malvin Medical Research Foundation (V.K.E.), New Orleans, Louisiana 70130; and Departments of Molecular and Cellular Biology (K.R., W.F., C.G., S.A.C., C.F., S.S.S., J.S., J.S.M., C.C., B.W.O., N.M.) and Department of Medicine (W.F., C.G., S.A.C., C.F., S.S.S., J.S., J.S.M., N.M.), Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Christopher
authors.initials: C
authors.lastname: Foley
authors.affiliation: Adrienne Helis Malvin Medical Research Foundation (V.K.E.), New Orleans, Louisiana 70130; and Departments of Molecular and Cellular Biology (K.R., W.F., C.G., S.A.C., C.F., S.S.S., J.S., J.S.M., C.C., B.W.O., N.M.) and Department of Medicine (W.F., C.G., S.A.C., C.F., S.S.S., J.S., J.S.M., N.M.), Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Shrijal S
authors.initials: SS
authors.lastname: Shah
authors.affiliation: Adrienne Helis Malvin Medical Research Foundation (V.K.E.), New Orleans, Louisiana 70130; and Departments of Molecular and Cellular Biology (K.R., W.F., C.G., S.A.C., C.F., S.S.S., J.S., J.S.M., C.C., B.W.O., N.M.) and Department of Medicine (W.F., C.G., S.A.C., C.F., S.S.S., J.S., J.S.M., N.M.), Baylor College of Medicine, Houston, Texas 77030.
authors.forename: John
authors.initials: J
authors.lastname: Shou
authors.affiliation: Adrienne Helis Malvin Medical Research Foundation (V.K.E.), New Orleans, Louisiana 70130; and Departments of Molecular and Cellular Biology (K.R., W.F., C.G., S.A.C., C.F., S.S.S., J.S., J.S.M., C.C., B.W.O., N.M.) and Department of Medicine (W.F., C.G., S.A.C., C.F., S.S.S., J.S., J.S.M., N.M.), Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Junaith S
authors.initials: JS
authors.lastname: Mohamed
authors.affiliation: Adrienne Helis Malvin Medical Research Foundation (V.K.E.), New Orleans, Louisiana 70130; and Departments of Molecular and Cellular Biology (K.R., W.F., C.G., S.A.C., C.F., S.S.S., J.S., J.S.M., C.C., B.W.O., N.M.) and Department of Medicine (W.F., C.G., S.A.C., C.F., S.S.S., J.S., J.S.M., N.M.), Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Cristian
authors.initials: C
authors.lastname: Coarfa
authors.affiliation: Adrienne Helis Malvin Medical Research Foundation (V.K.E.), New Orleans, Louisiana 70130; and Departments of Molecular and Cellular Biology (K.R., W.F., C.G., S.A.C., C.F., S.S.S., J.S., J.S.M., C.C., B.W.O., N.M.) and Department of Medicine (W.F., C.G., S.A.C., C.F., S.S.S., J.S., J.S.M., N.M.), Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Bert W
authors.initials: BW
authors.lastname: O'Malley
authors.affiliation: Adrienne Helis Malvin Medical Research Foundation (V.K.E.), New Orleans, Louisiana 70130; and Departments of Molecular and Cellular Biology (K.R., W.F., C.G., S.A.C., C.F., S.S.S., J.S., J.S.M., C.C., B.W.O., N.M.) and Department of Medicine (W.F., C.G., S.A.C., C.F., S.S.S., J.S., J.S.M., N.M.), Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Mitsiades
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019295:Computational Biology; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D057809:HEK293 Cells; D006657:Histones / Q000737:chemistry; D006801:Humans; D061986:MCF-7 Cells; D008297:Male; D035683:MicroRNAs / Q000378:metabolism*; D009154:Mutation; D056920:Nuclear Receptor Coactivator 1 / Q000378:metabolism*; D051958:Nuclear Receptor Coactivator 2 / Q000378:metabolism*; D056921:Nuclear Receptor Coactivator 3 / Q000378:metabolism*; D040901:Proteomics; D015533:Transcriptional Activation
chemical_list: D006657:Histones; C545567:MIRN137 microRNA, human; D035683:MicroRNAs; D051958:Nuclear Receptor Coactivator 2; C538859:NCOA1 protein, human; C538866:NCOA3 protein, human; D056920:Nuclear Receptor Coactivator 1; D056921:Nuclear Receptor Coactivator 3