Systematic analysis of microRNAs targeting the androgen receptor in prostate cancer cells

Päivi Östling, Suvi-Katri Leivonen, Anna Aakula, Pekka Kohonen, Rami Mäkelä, Zandra Hagman, Anders Edsjö, Sara Kangaspeska, Henrik Edgren, Daniel Nicorici, Anders Bjartell, Yvonne Ceder, Merja Perälä, Olli Kallioniemi

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Abstract

Androgen receptor (AR) is expressed in all stages of prostate cancer progression, including in castration-resistant tumors. Eliminating AR function continues to represent a focus of therapeutic investigation, but AR regulatory mechanisms remain poorly understood. To systematically characterize mechanisms involving microRNAs (miRNAs), we conducted a gain-of function screen of 1129 miRNA molecules in a panel of human prostate cancer cell lines and quantified changes in AR protein content using protein lysate microarrays. In this way, we defined 71 unique miRNAs that influenced the level of AR in human prostate cancer cells. RNA sequencing data revealed that the 3′UTR of AR (and other genes) is much longer than currently used in miRNA target prediction programs. Our own analyses predicted that most of the miRNA regulation of AR would target an extended 6 kb 3′UTR. 3′UTR-binding assays validated 13 miRNAs that are able to regulate this long AR 3′UTR (miR-135b, miR-185, miR-297, miR-299-3p, miR-34a, miR-34c, miR-371–3p, miR-421, miR-449a, miR-449b, miR-634, miR-654–5p, and miR-9). Fifteen AR downregulating miRNAs decreased androgen-induced proliferation of prostate cancer cells. In particular, analysis of clinical prostate cancers confirmed a negative correlation of miR-34a and miR-34c expression with AR levels. Our findings establish that miRNAs interacting with the long 3′UTR of the AR gene are important regulators of AR protein levels, with implications for developing new therapeutic strategies to inhibit AR function and androgen-dependent cell growth.
Original languageEnglish
Pages (from-to)1956-1967
JournalCancer Research
Volume71
Issue number5
DOIs
Publication statusPublished - 2011
MoE publication typeA1 Journal article-refereed

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Androgen Receptors
MicroRNAs
Prostatic Neoplasms
Androgens
RNA Sequence Analysis
Protein Array Analysis
Castration
Regulator Genes
Proteins
Down-Regulation

Keywords

  • microRNA
  • cancer
  • cancer cells
  • prostate cancer

Cite this

Östling, P., Leivonen, S-K., Aakula, A., Kohonen, P., Mäkelä, R., Hagman, Z., ... Kallioniemi, O. (2011). Systematic analysis of microRNAs targeting the androgen receptor in prostate cancer cells. Cancer Research, 71(5), 1956-1967. https://doi.org/10.1158/0008-5472.CAN-10-2421
Östling, Päivi ; Leivonen, Suvi-Katri ; Aakula, Anna ; Kohonen, Pekka ; Mäkelä, Rami ; Hagman, Zandra ; Edsjö, Anders ; Kangaspeska, Sara ; Edgren, Henrik ; Nicorici, Daniel ; Bjartell, Anders ; Ceder, Yvonne ; Perälä, Merja ; Kallioniemi, Olli. / Systematic analysis of microRNAs targeting the androgen receptor in prostate cancer cells. In: Cancer Research. 2011 ; Vol. 71, No. 5. pp. 1956-1967.
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abstract = "Androgen receptor (AR) is expressed in all stages of prostate cancer progression, including in castration-resistant tumors. Eliminating AR function continues to represent a focus of therapeutic investigation, but AR regulatory mechanisms remain poorly understood. To systematically characterize mechanisms involving microRNAs (miRNAs), we conducted a gain-of function screen of 1129 miRNA molecules in a panel of human prostate cancer cell lines and quantified changes in AR protein content using protein lysate microarrays. In this way, we defined 71 unique miRNAs that influenced the level of AR in human prostate cancer cells. RNA sequencing data revealed that the 3′UTR of AR (and other genes) is much longer than currently used in miRNA target prediction programs. Our own analyses predicted that most of the miRNA regulation of AR would target an extended 6 kb 3′UTR. 3′UTR-binding assays validated 13 miRNAs that are able to regulate this long AR 3′UTR (miR-135b, miR-185, miR-297, miR-299-3p, miR-34a, miR-34c, miR-371–3p, miR-421, miR-449a, miR-449b, miR-634, miR-654–5p, and miR-9). Fifteen AR downregulating miRNAs decreased androgen-induced proliferation of prostate cancer cells. In particular, analysis of clinical prostate cancers confirmed a negative correlation of miR-34a and miR-34c expression with AR levels. Our findings establish that miRNAs interacting with the long 3′UTR of the AR gene are important regulators of AR protein levels, with implications for developing new therapeutic strategies to inhibit AR function and androgen-dependent cell growth.",
keywords = "microRNA, cancer, cancer cells, prostate cancer",
author = "P{\"a}ivi {\"O}stling and Suvi-Katri Leivonen and Anna Aakula and Pekka Kohonen and Rami M{\"a}kel{\"a} and Zandra Hagman and Anders Edsj{\"o} and Sara Kangaspeska and Henrik Edgren and Daniel Nicorici and Anders Bjartell and Yvonne Ceder and Merja Per{\"a}l{\"a} and Olli Kallioniemi",
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Östling, P, Leivonen, S-K, Aakula, A, Kohonen, P, Mäkelä, R, Hagman, Z, Edsjö, A, Kangaspeska, S, Edgren, H, Nicorici, D, Bjartell, A, Ceder, Y, Perälä, M & Kallioniemi, O 2011, 'Systematic analysis of microRNAs targeting the androgen receptor in prostate cancer cells', Cancer Research, vol. 71, no. 5, pp. 1956-1967. https://doi.org/10.1158/0008-5472.CAN-10-2421

Systematic analysis of microRNAs targeting the androgen receptor in prostate cancer cells. / Östling, Päivi; Leivonen, Suvi-Katri; Aakula, Anna; Kohonen, Pekka; Mäkelä, Rami; Hagman, Zandra; Edsjö, Anders; Kangaspeska, Sara; Edgren, Henrik; Nicorici, Daniel; Bjartell, Anders; Ceder, Yvonne; Perälä, Merja; Kallioniemi, Olli.

In: Cancer Research, Vol. 71, No. 5, 2011, p. 1956-1967.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Systematic analysis of microRNAs targeting the androgen receptor in prostate cancer cells

AU - Östling, Päivi

AU - Leivonen, Suvi-Katri

AU - Aakula, Anna

AU - Kohonen, Pekka

AU - Mäkelä, Rami

AU - Hagman, Zandra

AU - Edsjö, Anders

AU - Kangaspeska, Sara

AU - Edgren, Henrik

AU - Nicorici, Daniel

AU - Bjartell, Anders

AU - Ceder, Yvonne

AU - Perälä, Merja

AU - Kallioniemi, Olli

PY - 2011

Y1 - 2011

N2 - Androgen receptor (AR) is expressed in all stages of prostate cancer progression, including in castration-resistant tumors. Eliminating AR function continues to represent a focus of therapeutic investigation, but AR regulatory mechanisms remain poorly understood. To systematically characterize mechanisms involving microRNAs (miRNAs), we conducted a gain-of function screen of 1129 miRNA molecules in a panel of human prostate cancer cell lines and quantified changes in AR protein content using protein lysate microarrays. In this way, we defined 71 unique miRNAs that influenced the level of AR in human prostate cancer cells. RNA sequencing data revealed that the 3′UTR of AR (and other genes) is much longer than currently used in miRNA target prediction programs. Our own analyses predicted that most of the miRNA regulation of AR would target an extended 6 kb 3′UTR. 3′UTR-binding assays validated 13 miRNAs that are able to regulate this long AR 3′UTR (miR-135b, miR-185, miR-297, miR-299-3p, miR-34a, miR-34c, miR-371–3p, miR-421, miR-449a, miR-449b, miR-634, miR-654–5p, and miR-9). Fifteen AR downregulating miRNAs decreased androgen-induced proliferation of prostate cancer cells. In particular, analysis of clinical prostate cancers confirmed a negative correlation of miR-34a and miR-34c expression with AR levels. Our findings establish that miRNAs interacting with the long 3′UTR of the AR gene are important regulators of AR protein levels, with implications for developing new therapeutic strategies to inhibit AR function and androgen-dependent cell growth.

AB - Androgen receptor (AR) is expressed in all stages of prostate cancer progression, including in castration-resistant tumors. Eliminating AR function continues to represent a focus of therapeutic investigation, but AR regulatory mechanisms remain poorly understood. To systematically characterize mechanisms involving microRNAs (miRNAs), we conducted a gain-of function screen of 1129 miRNA molecules in a panel of human prostate cancer cell lines and quantified changes in AR protein content using protein lysate microarrays. In this way, we defined 71 unique miRNAs that influenced the level of AR in human prostate cancer cells. RNA sequencing data revealed that the 3′UTR of AR (and other genes) is much longer than currently used in miRNA target prediction programs. Our own analyses predicted that most of the miRNA regulation of AR would target an extended 6 kb 3′UTR. 3′UTR-binding assays validated 13 miRNAs that are able to regulate this long AR 3′UTR (miR-135b, miR-185, miR-297, miR-299-3p, miR-34a, miR-34c, miR-371–3p, miR-421, miR-449a, miR-449b, miR-634, miR-654–5p, and miR-9). Fifteen AR downregulating miRNAs decreased androgen-induced proliferation of prostate cancer cells. In particular, analysis of clinical prostate cancers confirmed a negative correlation of miR-34a and miR-34c expression with AR levels. Our findings establish that miRNAs interacting with the long 3′UTR of the AR gene are important regulators of AR protein levels, with implications for developing new therapeutic strategies to inhibit AR function and androgen-dependent cell growth.

KW - microRNA

KW - cancer

KW - cancer cells

KW - prostate cancer

U2 - 10.1158/0008-5472.CAN-10-2421

DO - 10.1158/0008-5472.CAN-10-2421

M3 - Article

VL - 71

SP - 1956

EP - 1967

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

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ER -

Östling P, Leivonen S-K, Aakula A, Kohonen P, Mäkelä R, Hagman Z et al. Systematic analysis of microRNAs targeting the androgen receptor in prostate cancer cells. Cancer Research. 2011;71(5):1956-1967. https://doi.org/10.1158/0008-5472.CAN-10-2421