MicroRNA let-7c suppresses androgen receptor expression and activity via regulation of myc expression in prostate cancer cells

N. Nadiminty, R. Tummala, W. Lou, Y. Zhu, J. Zhang, X. Chen, R.W. DeVere White, H.-J. Kung, C.P. Evans, A.C. Gao

Research output: Contribution to journalArticle

129 Citations (Scopus)

Abstract

Castration-resistant prostate cancer continues to rely on androgen receptor (AR) expression. AR plays a central role in the development of prostate cancer and progression to castration resistance during and after androgen deprivation therapy. Here, we identified miR-let-7c as a key regulator of expression of AR. miR-let-7c suppresses AR expression and activity in human prostate cancer cells by targeting its transcription via c-Myc. Suppression of AR by let-7c leads to decreased cell proliferation of human prostate cancer cells. Down-regulation of Let-7c in prostate cancer specimens is inversely correlated with AR expression, whereas the expression of Lin28 (a repressor of let-7) is correlated positively with AR expression. Our study demonstrates that the miRNA let-7c plays an important role in the regulation of androgen signaling in prostate cancer by down-regulating AR expression. These results suggest that reconstitution of miR-let-7c may aid in targeting enhanced and hypersensitive AR in advanced prostate cancer. © 2012 by The American Society for Biochemistry and Molecular Biology, Inc.
Original languageEnglish
Pages (from-to)1527-1537
Number of pages11
JournalJournal of Biological Chemistry
Volume287
Issue number2
DOIs
Publication statusPublished - Jan 2012
Externally publishedYes

Fingerprint

Androgen Receptors
MicroRNAs
Prostatic Neoplasms
Cells
Castration
Androgens
Cell proliferation
Transcription
Human Activities
Down-Regulation
Cell Proliferation

Keywords

  • Androgen deprivation therapy
  • Androgen receptors
  • Down-regulation
  • Human prostate cancer cells
  • Key regulators
  • MicroRNAs
  • Prostate cancer cells
  • Prostate cancers
  • Cell proliferation
  • Cells
  • Diseases
  • androgen receptor
  • microRNA
  • microRNA let 7c
  • Myc protein
  • unclassified drug
  • article
  • binding site
  • cancer cell culture
  • cell proliferation
  • cell survival
  • chromatin immunoprecipitation
  • controlled study
  • down regulation
  • enzyme reconstitution
  • gene expression regulation
  • gene overexpression
  • genetic transcription
  • human
  • human cell
  • plasmid
  • priority journal
  • promoter region
  • prostate cancer
  • protein analysis
  • protein binding
  • signal transduction
  • upregulation
  • Cell Line, Tumor
  • Cell Proliferation
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Male
  • Prostatic Neoplasms
  • Proto-Oncogene Proteins c-myc
  • Receptors, Androgen
  • RNA, Neoplasm
  • RNA-Binding Proteins
  • Signal Transduction

Cite this

MicroRNA let-7c suppresses androgen receptor expression and activity via regulation of myc expression in prostate cancer cells. / Nadiminty, N.; Tummala, R.; Lou, W.; Zhu, Y.; Zhang, J.; Chen, X.; DeVere White, R.W.; Kung, H.-J.; Evans, C.P.; Gao, A.C.

In: Journal of Biological Chemistry, Vol. 287, No. 2, 01.2012, p. 1527-1537.

Research output: Contribution to journalArticle

Nadiminty, N, Tummala, R, Lou, W, Zhu, Y, Zhang, J, Chen, X, DeVere White, RW, Kung, H-J, Evans, CP & Gao, AC 2012, 'MicroRNA let-7c suppresses androgen receptor expression and activity via regulation of myc expression in prostate cancer cells', Journal of Biological Chemistry, vol. 287, no. 2, pp. 1527-1537. https://doi.org/10.1074/jbc.M111.278705
Nadiminty, N. ; Tummala, R. ; Lou, W. ; Zhu, Y. ; Zhang, J. ; Chen, X. ; DeVere White, R.W. ; Kung, H.-J. ; Evans, C.P. ; Gao, A.C. / MicroRNA let-7c suppresses androgen receptor expression and activity via regulation of myc expression in prostate cancer cells. In: Journal of Biological Chemistry. 2012 ; Vol. 287, No. 2. pp. 1527-1537.
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title = "MicroRNA let-7c suppresses androgen receptor expression and activity via regulation of myc expression in prostate cancer cells",
abstract = "Castration-resistant prostate cancer continues to rely on androgen receptor (AR) expression. AR plays a central role in the development of prostate cancer and progression to castration resistance during and after androgen deprivation therapy. Here, we identified miR-let-7c as a key regulator of expression of AR. miR-let-7c suppresses AR expression and activity in human prostate cancer cells by targeting its transcription via c-Myc. Suppression of AR by let-7c leads to decreased cell proliferation of human prostate cancer cells. Down-regulation of Let-7c in prostate cancer specimens is inversely correlated with AR expression, whereas the expression of Lin28 (a repressor of let-7) is correlated positively with AR expression. Our study demonstrates that the miRNA let-7c plays an important role in the regulation of androgen signaling in prostate cancer by down-regulating AR expression. These results suggest that reconstitution of miR-let-7c may aid in targeting enhanced and hypersensitive AR in advanced prostate cancer. {\circledC} 2012 by The American Society for Biochemistry and Molecular Biology, Inc.",
keywords = "Androgen deprivation therapy, Androgen receptors, Down-regulation, Human prostate cancer cells, Key regulators, MicroRNAs, Prostate cancer cells, Prostate cancers, Cell proliferation, Cells, Diseases, androgen receptor, microRNA, microRNA let 7c, Myc protein, unclassified drug, article, binding site, cancer cell culture, cell proliferation, cell survival, chromatin immunoprecipitation, controlled study, down regulation, enzyme reconstitution, gene expression regulation, gene overexpression, genetic transcription, human, human cell, plasmid, priority journal, promoter region, prostate cancer, protein analysis, protein binding, signal transduction, upregulation, Cell Line, Tumor, Cell Proliferation, Gene Expression Regulation, Neoplastic, Humans, Male, Prostatic Neoplasms, Proto-Oncogene Proteins c-myc, Receptors, Androgen, RNA, Neoplasm, RNA-Binding Proteins, Signal Transduction",
author = "N. Nadiminty and R. Tummala and W. Lou and Y. Zhu and J. Zhang and X. Chen and {DeVere White}, R.W. and H.-J. Kung and C.P. Evans and A.C. Gao",
note = "引用次數:103 Export Date: 5 March 2018 CODEN: JBCHA 通訊地址: Nadiminty, N.; Department of Urology, University of California Davis Medical Center, Research III, 4645 2nd Ave, Sacramento, CA 95817, United States; 電子郵件: nnadiminty@ucdavis.edu 化學物質/CAS: LIN-28 protein, human; MYC protein, human; MicroRNAs; Proto-Oncogene Proteins c-myc; RNA, Neoplasm; RNA-Binding Proteins; Receptors, Androgen; mirnlet7 microRNA, human 參考文獻: Chen, Y., Sawyers, C.L., Scher, H.I., Targeting the androgen receptor pathway in prostate cancer (2008) Curr. Opin. Pharmacol., 8, pp. 440-448; Lamont, K.R., Tindall, D.J., Androgen regulation of gene expression (2010) Adv. Cancer Res., 107, pp. 137-162; Coppola, V., De Maria, R., Bonci, D., (2010) Endocr. Relat. Cancer, 17, pp. F1-F17; Shi, X.B., Tepper, C.G., DeVere White, R.W., Cancerous miRNAs and their regulation (2008) Cell Cycle, 7, pp. 1529-1538; Gandellini, P., Folini, M., Zaffaroni, N., Towards the definition of prostate cancer-related microRNAs. Where are we now? (2009) Trends Mol. Med., 15, pp. 381-390; Calin, G.A., Sevignani, C., Dumitru, C.D., Hyslop, T., Noch, E., Yendamuri, S., Shimizu, M., Croce, C.M., Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers (2004) Proc. Natl. Acad. Sci. U.S.A., 101, pp. 2999-3004; Ozen, M., Creighton, C.J., Ozdemir, M., Ittmann, M., Widespread deregulation of microRNA expression in human prostate cancer (2008) Oncogene, 27, pp. 1788-1793; Jiang, J., Lee, E.J., Gusev, Y., Schmittgen, T.D., Real-time expression profiling of microRNA precursors in human cancer cell lines (2005) Nucleic Acids Res., 33, pp. 5394-5403; Boyerinas, B., Park, S.M., Hau, A., Murmann, A.E., Peter, M.E., The role of let-7 in cell differentiation and cancer (2010) Endocr. Relat. Cancer, 17, pp. F19-F36; Lee, Y.S., Dutta, A., The tumor suppressor microRNA let-7 represses the HMGA2 oncogene (2007) Genes Dev., 21, pp. 1025-1030; Johnson, S.M., Grosshans, H., Shingara, J., Byrom, M., Jarvis, R., Cheng, A., Labourier, E., Slack, F.J., RAS is regulated by the let-7 microRNA family (2005) Cell, 120, pp. 635-647; Kumar, M.S., Lu, J., Mercer, K.L., Golub, T.R., Jacks, T., Impaired microRNA processing enhances cellular transformation and tumorigenesis (2007) Nat. Genet., 39, pp. 673-677; Viswanathan, S.R., Daley, G.Q., Gregory, R.I., Selective blockade of microRNA processing by Lin28 (2008) Science, 320, pp. 97-100; Viswanathan, S.R., Daley, G.Q., Lin28. A microRNA regulator with a macro role (2010) Cell, 140, pp. 445-449; Chang, T.C., Zeitels, L.R., Hwang, H.W., Chivukula, R.R., Wentzel, E.A., Dews, M., Jung, J., Mendell, J.T., Lin-28B transactivation is necessary for Myc-mediated let-7 repression and proliferation (2009) Proc. Natl. Acad. Sci. U.S.A., 106, pp. 3384-3389; Dangi-Garimella, S., Yun, J., Eves, E.M., Newman, M., Erkeland, S.J., Hammond, S.M., Minn, A.J., Rosner, M.R., Raf kinase inhibitory protein suppresses a metastasis signalling cascade involving LIN28 and let-7 (2009) EMBO J., 28, pp. 347-358; Lu, J., Getz, G., Miska, E.A., Alvarez-Saavedra, E., Lamb, J., Peck, D., Sweet-Cordero, A., Golub, T.R., MicroRNA expression profiles classify human cancers (2005) Nature, 435, pp. 834-838; Nadiminty, N., Lou, W., Lee, S.O., Lin, X., Trump, D.L., Gao, A.C., Stat3 activation of NF-κB p100 processing involves CBP/p300-mediated acetylation (2006) Proc. Natl. Acad. Sci. U.S.A., 103, pp. 7264-7269; Nadiminty, N., Dutt, S., Tepper, C., Gao, A.C., Microarray analysis reveals potential target genes of NF-κB2/p52 in LNCaP prostate cancer cells (2010) Prostate, 70, pp. 276-287; Nadiminty, N., Lou, W., Sun, M., Chen, J., Yue, J., Kung, H.J., Evans, C.P., Gao, A.C., Aberrant activation of the androgen receptor by NF-κB2/p52 in prostate cancer cells (2010) Cancer Res., 70, pp. 3309-3319; Dhir, R., Ni, Z., Lou, W., DeMiguel, F., Grandis, J.R., Gao, A.C., Stat3 activation in prostatic carcinomas (2002) Prostate, 51, pp. 241-246; Ni, Z., Lou, W., Lee, S.O., Dhir, R., DeMiguel, F., Grandis, J.R., Gao, A.C., Selective activation of members of the signal transducers and activators of transcription family in prostate carcinoma (2002) J. Urol., 167, pp. 1859-1862; Varambally, S., Yu, J., Laxman, B., Rhodes, D.R., Mehra, R., Tomlins, S.A., Shah, R.B., Chinnaiyan, A.M., Integrative genomic and proteomic analysis of prostate cancer reveals signatures of metastatic progression (2005) Cancer Cell, 8, pp. 393-406; Chandran, U.R., Ma, C., Dhir, R., Bisceglia, M., Lyons-Weiler, M., Liang, W., Michalopoulos, G., Monzon, F.A., Gene expression profiles of prostate cancer reveal involvement of multiple molecular pathways in the metastatic process (2007) BMC Cancer, 7, p. 64; Prasad, P.D., Stanton, J.A., Assinder, S.J., Expression of the actin-associated protein transgelin (SM22) is decreased in prostate cancer (2010) Cell Tissue Res., 339, pp. 337-347; Wallace, T.A., Prueitt, R.L., Yi, M., Howe, T.M., Gillespie, J.W., Yfantis, H.G., Stephens, R.M., Ambs, S., Tumor immunobiological differences in prostate cancer between African-American and European-American men (2008) Cancer Res., 68, pp. 927-936; Yu, Y.P., Landsittel, D., Jing, L., Nelson, J., Ren, B., Liu, L., McDonald, C., Luo, J.H., Gene expression alterations in prostate cancer predicting tumor aggression and preceding development of malignancy (2004) J. Clin. Oncology, 22, pp. 2790-2799; Vanaja, D.K., Cheville, J.C., Iturria, S.J., Young, C.Y., Transcriptional silencing of zinc finger protein 185 identified by expression profiling is associated with prostate cancer progression (2003) Cancer Res., 63, pp. 3877-3882; Lee, S.O., Lou, W., Hou, M., De Miguel, F., Gerber, L., Gao, A.C., Interleukin-6 promotes androgen-independent growth in LNCaP human prostate cancer cells (2003) Clin. Cancer Res., 9, pp. 370-376; Lee, S.O., Chun, J.Y., Nadiminty, N., Lou, W., Gao, A.C., Interleukin-6 undergoes transition from growth inhibitor associated with neuroendocrine differentiation to stimulator accompanied by androgen receptor activation during LNCaP prostate cancer cell progression (2007) Prostate, 67, pp. 764-773; Koscianska, E., Baev, V., Skreka, K., Oikonomaki, K., Rusinov, V., Tabler, M., Kalantidis, K., Prediction and preliminary validation of oncogene regulation by miRNAs (2007) BMC Mol. Biol., 8, p. 79; Iliopoulos, D., Hirsch, H.A., Struhl, K., An epigenetic switch involving NF-κB, Lin28, Let-7 MicroRNA, and IL6 links inflammation to cell transformation (2009) Cell, 139, pp. 693-706; Chen, C.D., Welsbie, D.S., Tran, C., Baek, S.H., Chen, R., Vessella, R., Rosenfeld, M.G., Sawyers, C.L., Molecular determinants of resistance to antiandrogen therapy (2004) Nat. Med., 10, pp. 33-39; Bonkhoff, H., Berges, R., From pathogenesis to prevention of castration-resistant prostate cancer (2010) Prostate, 70, pp. 100-112; Donovan, M.J., Khan, F.M., Fernandez, G., Mesa-Tejada, R., Sapir, M., Zubek, V.B., Powell, D., Cordon-Cardo, C., Personalized prediction of tumor response and cancer progression on prostate needle biopsy (2009) J. Urol., 182, pp. 125-132; Heinlein, C.A., Chang, C., Androgen receptor in prostate cancer (2004) Endocr. Rev., 25, pp. 276-308; Singh, P., Uzgare, A., Litvinov, I., Denmeade, S.R., Isaacs, J.T., Combinatorial androgen receptor-targeted therapy for prostate cancer (2006) Endocr. Relat. Cancer, 13, pp. 653-666; Pienta, K.J., Bradley, D., Mechanisms underlying the development of androgen-independent prostate cancer (2006) Clin. Cancer Res., 12, pp. 1665-1671; Tran, C., Ouk, S., Clegg, N.J., Chen, Y., Watson, P.A., Arora, V., Wongvipat, J., Sawyers, C.L., Development of a second-generation antiandrogen for treatment of advanced prostate cancer (2009) Science, 324, pp. 787-790",
year = "2012",
month = "1",
doi = "10.1074/jbc.M111.278705",
language = "English",
volume = "287",
pages = "1527--1537",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "2",

}

TY - JOUR

T1 - MicroRNA let-7c suppresses androgen receptor expression and activity via regulation of myc expression in prostate cancer cells

AU - Nadiminty, N.

AU - Tummala, R.

AU - Lou, W.

AU - Zhu, Y.

AU - Zhang, J.

AU - Chen, X.

AU - DeVere White, R.W.

AU - Kung, H.-J.

AU - Evans, C.P.

AU - Gao, A.C.

N1 - 引用次數:103 Export Date: 5 March 2018 CODEN: JBCHA 通訊地址: Nadiminty, N.; Department of Urology, University of California Davis Medical Center, Research III, 4645 2nd Ave, Sacramento, CA 95817, United States; 電子郵件: nnadiminty@ucdavis.edu 化學物質/CAS: LIN-28 protein, human; MYC protein, human; MicroRNAs; Proto-Oncogene Proteins c-myc; RNA, Neoplasm; RNA-Binding Proteins; Receptors, Androgen; mirnlet7 microRNA, human 參考文獻: Chen, Y., Sawyers, C.L., Scher, H.I., Targeting the androgen receptor pathway in prostate cancer (2008) Curr. Opin. Pharmacol., 8, pp. 440-448; Lamont, K.R., Tindall, D.J., Androgen regulation of gene expression (2010) Adv. Cancer Res., 107, pp. 137-162; Coppola, V., De Maria, R., Bonci, D., (2010) Endocr. Relat. Cancer, 17, pp. F1-F17; Shi, X.B., Tepper, C.G., DeVere White, R.W., Cancerous miRNAs and their regulation (2008) Cell Cycle, 7, pp. 1529-1538; Gandellini, P., Folini, M., Zaffaroni, N., Towards the definition of prostate cancer-related microRNAs. Where are we now? (2009) Trends Mol. Med., 15, pp. 381-390; Calin, G.A., Sevignani, C., Dumitru, C.D., Hyslop, T., Noch, E., Yendamuri, S., Shimizu, M., Croce, C.M., Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers (2004) Proc. Natl. Acad. Sci. U.S.A., 101, pp. 2999-3004; Ozen, M., Creighton, C.J., Ozdemir, M., Ittmann, M., Widespread deregulation of microRNA expression in human prostate cancer (2008) Oncogene, 27, pp. 1788-1793; Jiang, J., Lee, E.J., Gusev, Y., Schmittgen, T.D., Real-time expression profiling of microRNA precursors in human cancer cell lines (2005) Nucleic Acids Res., 33, pp. 5394-5403; Boyerinas, B., Park, S.M., Hau, A., Murmann, A.E., Peter, M.E., The role of let-7 in cell differentiation and cancer (2010) Endocr. Relat. Cancer, 17, pp. F19-F36; Lee, Y.S., Dutta, A., The tumor suppressor microRNA let-7 represses the HMGA2 oncogene (2007) Genes Dev., 21, pp. 1025-1030; Johnson, S.M., Grosshans, H., Shingara, J., Byrom, M., Jarvis, R., Cheng, A., Labourier, E., Slack, F.J., RAS is regulated by the let-7 microRNA family (2005) Cell, 120, pp. 635-647; Kumar, M.S., Lu, J., Mercer, K.L., Golub, T.R., Jacks, T., Impaired microRNA processing enhances cellular transformation and tumorigenesis (2007) Nat. Genet., 39, pp. 673-677; Viswanathan, S.R., Daley, G.Q., Gregory, R.I., Selective blockade of microRNA processing by Lin28 (2008) Science, 320, pp. 97-100; Viswanathan, S.R., Daley, G.Q., Lin28. A microRNA regulator with a macro role (2010) Cell, 140, pp. 445-449; Chang, T.C., Zeitels, L.R., Hwang, H.W., Chivukula, R.R., Wentzel, E.A., Dews, M., Jung, J., Mendell, J.T., Lin-28B transactivation is necessary for Myc-mediated let-7 repression and proliferation (2009) Proc. Natl. Acad. Sci. U.S.A., 106, pp. 3384-3389; Dangi-Garimella, S., Yun, J., Eves, E.M., Newman, M., Erkeland, S.J., Hammond, S.M., Minn, A.J., Rosner, M.R., Raf kinase inhibitory protein suppresses a metastasis signalling cascade involving LIN28 and let-7 (2009) EMBO J., 28, pp. 347-358; Lu, J., Getz, G., Miska, E.A., Alvarez-Saavedra, E., Lamb, J., Peck, D., Sweet-Cordero, A., Golub, T.R., MicroRNA expression profiles classify human cancers (2005) Nature, 435, pp. 834-838; Nadiminty, N., Lou, W., Lee, S.O., Lin, X., Trump, D.L., Gao, A.C., Stat3 activation of NF-κB p100 processing involves CBP/p300-mediated acetylation (2006) Proc. Natl. Acad. Sci. U.S.A., 103, pp. 7264-7269; Nadiminty, N., Dutt, S., Tepper, C., Gao, A.C., Microarray analysis reveals potential target genes of NF-κB2/p52 in LNCaP prostate cancer cells (2010) Prostate, 70, pp. 276-287; Nadiminty, N., Lou, W., Sun, M., Chen, J., Yue, J., Kung, H.J., Evans, C.P., Gao, A.C., Aberrant activation of the androgen receptor by NF-κB2/p52 in prostate cancer cells (2010) Cancer Res., 70, pp. 3309-3319; Dhir, R., Ni, Z., Lou, W., DeMiguel, F., Grandis, J.R., Gao, A.C., Stat3 activation in prostatic carcinomas (2002) Prostate, 51, pp. 241-246; Ni, Z., Lou, W., Lee, S.O., Dhir, R., DeMiguel, F., Grandis, J.R., Gao, A.C., Selective activation of members of the signal transducers and activators of transcription family in prostate carcinoma (2002) J. Urol., 167, pp. 1859-1862; Varambally, S., Yu, J., Laxman, B., Rhodes, D.R., Mehra, R., Tomlins, S.A., Shah, R.B., Chinnaiyan, A.M., Integrative genomic and proteomic analysis of prostate cancer reveals signatures of metastatic progression (2005) Cancer Cell, 8, pp. 393-406; Chandran, U.R., Ma, C., Dhir, R., Bisceglia, M., Lyons-Weiler, M., Liang, W., Michalopoulos, G., Monzon, F.A., Gene expression profiles of prostate cancer reveal involvement of multiple molecular pathways in the metastatic process (2007) BMC Cancer, 7, p. 64; Prasad, P.D., Stanton, J.A., Assinder, S.J., Expression of the actin-associated protein transgelin (SM22) is decreased in prostate cancer (2010) Cell Tissue Res., 339, pp. 337-347; Wallace, T.A., Prueitt, R.L., Yi, M., Howe, T.M., Gillespie, J.W., Yfantis, H.G., Stephens, R.M., Ambs, S., Tumor immunobiological differences in prostate cancer between African-American and European-American men (2008) Cancer Res., 68, pp. 927-936; Yu, Y.P., Landsittel, D., Jing, L., Nelson, J., Ren, B., Liu, L., McDonald, C., Luo, J.H., Gene expression alterations in prostate cancer predicting tumor aggression and preceding development of malignancy (2004) J. Clin. Oncology, 22, pp. 2790-2799; Vanaja, D.K., Cheville, J.C., Iturria, S.J., Young, C.Y., Transcriptional silencing of zinc finger protein 185 identified by expression profiling is associated with prostate cancer progression (2003) Cancer Res., 63, pp. 3877-3882; Lee, S.O., Lou, W., Hou, M., De Miguel, F., Gerber, L., Gao, A.C., Interleukin-6 promotes androgen-independent growth in LNCaP human prostate cancer cells (2003) Clin. Cancer Res., 9, pp. 370-376; Lee, S.O., Chun, J.Y., Nadiminty, N., Lou, W., Gao, A.C., Interleukin-6 undergoes transition from growth inhibitor associated with neuroendocrine differentiation to stimulator accompanied by androgen receptor activation during LNCaP prostate cancer cell progression (2007) Prostate, 67, pp. 764-773; Koscianska, E., Baev, V., Skreka, K., Oikonomaki, K., Rusinov, V., Tabler, M., Kalantidis, K., Prediction and preliminary validation of oncogene regulation by miRNAs (2007) BMC Mol. Biol., 8, p. 79; Iliopoulos, D., Hirsch, H.A., Struhl, K., An epigenetic switch involving NF-κB, Lin28, Let-7 MicroRNA, and IL6 links inflammation to cell transformation (2009) Cell, 139, pp. 693-706; Chen, C.D., Welsbie, D.S., Tran, C., Baek, S.H., Chen, R., Vessella, R., Rosenfeld, M.G., Sawyers, C.L., Molecular determinants of resistance to antiandrogen therapy (2004) Nat. Med., 10, pp. 33-39; Bonkhoff, H., Berges, R., From pathogenesis to prevention of castration-resistant prostate cancer (2010) Prostate, 70, pp. 100-112; Donovan, M.J., Khan, F.M., Fernandez, G., Mesa-Tejada, R., Sapir, M., Zubek, V.B., Powell, D., Cordon-Cardo, C., Personalized prediction of tumor response and cancer progression on prostate needle biopsy (2009) J. Urol., 182, pp. 125-132; Heinlein, C.A., Chang, C., Androgen receptor in prostate cancer (2004) Endocr. Rev., 25, pp. 276-308; Singh, P., Uzgare, A., Litvinov, I., Denmeade, S.R., Isaacs, J.T., Combinatorial androgen receptor-targeted therapy for prostate cancer (2006) Endocr. Relat. Cancer, 13, pp. 653-666; Pienta, K.J., Bradley, D., Mechanisms underlying the development of androgen-independent prostate cancer (2006) Clin. Cancer Res., 12, pp. 1665-1671; Tran, C., Ouk, S., Clegg, N.J., Chen, Y., Watson, P.A., Arora, V., Wongvipat, J., Sawyers, C.L., Development of a second-generation antiandrogen for treatment of advanced prostate cancer (2009) Science, 324, pp. 787-790

PY - 2012/1

Y1 - 2012/1

N2 - Castration-resistant prostate cancer continues to rely on androgen receptor (AR) expression. AR plays a central role in the development of prostate cancer and progression to castration resistance during and after androgen deprivation therapy. Here, we identified miR-let-7c as a key regulator of expression of AR. miR-let-7c suppresses AR expression and activity in human prostate cancer cells by targeting its transcription via c-Myc. Suppression of AR by let-7c leads to decreased cell proliferation of human prostate cancer cells. Down-regulation of Let-7c in prostate cancer specimens is inversely correlated with AR expression, whereas the expression of Lin28 (a repressor of let-7) is correlated positively with AR expression. Our study demonstrates that the miRNA let-7c plays an important role in the regulation of androgen signaling in prostate cancer by down-regulating AR expression. These results suggest that reconstitution of miR-let-7c may aid in targeting enhanced and hypersensitive AR in advanced prostate cancer. © 2012 by The American Society for Biochemistry and Molecular Biology, Inc.

AB - Castration-resistant prostate cancer continues to rely on androgen receptor (AR) expression. AR plays a central role in the development of prostate cancer and progression to castration resistance during and after androgen deprivation therapy. Here, we identified miR-let-7c as a key regulator of expression of AR. miR-let-7c suppresses AR expression and activity in human prostate cancer cells by targeting its transcription via c-Myc. Suppression of AR by let-7c leads to decreased cell proliferation of human prostate cancer cells. Down-regulation of Let-7c in prostate cancer specimens is inversely correlated with AR expression, whereas the expression of Lin28 (a repressor of let-7) is correlated positively with AR expression. Our study demonstrates that the miRNA let-7c plays an important role in the regulation of androgen signaling in prostate cancer by down-regulating AR expression. These results suggest that reconstitution of miR-let-7c may aid in targeting enhanced and hypersensitive AR in advanced prostate cancer. © 2012 by The American Society for Biochemistry and Molecular Biology, Inc.

KW - Androgen deprivation therapy

KW - Androgen receptors

KW - Down-regulation

KW - Human prostate cancer cells

KW - Key regulators

KW - MicroRNAs

KW - Prostate cancer cells

KW - Prostate cancers

KW - Cell proliferation

KW - Cells

KW - Diseases

KW - androgen receptor

KW - microRNA

KW - microRNA let 7c

KW - Myc protein

KW - unclassified drug

KW - article

KW - binding site

KW - cancer cell culture

KW - cell proliferation

KW - cell survival

KW - chromatin immunoprecipitation

KW - controlled study

KW - down regulation

KW - enzyme reconstitution

KW - gene expression regulation

KW - gene overexpression

KW - genetic transcription

KW - human

KW - human cell

KW - plasmid

KW - priority journal

KW - promoter region

KW - prostate cancer

KW - protein analysis

KW - protein binding

KW - signal transduction

KW - upregulation

KW - Cell Line, Tumor

KW - Cell Proliferation

KW - Gene Expression Regulation, Neoplastic

KW - Humans

KW - Male

KW - Prostatic Neoplasms

KW - Proto-Oncogene Proteins c-myc

KW - Receptors, Androgen

KW - RNA, Neoplasm

KW - RNA-Binding Proteins

KW - Signal Transduction

U2 - 10.1074/jbc.M111.278705

DO - 10.1074/jbc.M111.278705

M3 - Article

VL - 287

SP - 1527

EP - 1537

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 2

ER -