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

Research output: Contribution to conferenceConference articleScientific

Abstract

Androgen receptor (AR) is expressed in all stages of prostate cancer progression and its levels increase in the castration-resistant tumors. However, the mechanisms regulating AR expression remain poorly understood. Here, our aim was to determine the role of miRNAs in regulating AR protein. To this end, we performed a systematic gain-of function screen for 1129 miRNA molecules in prostate cancer cell lines and quantified changes in AR protein content using protein lysate microarrays. We identified 71 unique miRNAs that influenced the level of AR in LNCaP, LAPC-4, 22Rv1, CWR-1R and MDA-PCa-2B cells. Our RNA-sequencing data showed that the 3'UTRs of many genes, including the AR, are much longer than currently used by target prediction programs. Our analyses predicted that the majority of the miRNA regulation of AR would occur through the extended 6 kb 3'UTR. 3'UTR-binding assays validated 13 miRNAs (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) as direct AR regulators. Fifteen AR down-regulating miRNAs decreased androgen-induced proliferation of prostate cancer cells in vitro. Negative correlation of miR-34a and miR-34c expression with AR levels was also found in clinical prostate cancers. To conclude, our results demonstrate that miRNAs interacting with the long 3'UTR of the AR gene are important regulators of AR protein levels. This could be applied for developing novel therapeutic strategies to inhibit AR function and androgen-dependent cell growth.
Original languageEnglish
Publication statusPublished - 2010
MoE publication typeNot Eligible
EventEMBO-EMBL Symposium - The Non-Coding Genome - EMBL Advanced Training Centre, Heidelberg, Germany
Duration: 13 Oct 201016 Oct 2010

Conference

ConferenceEMBO-EMBL Symposium - The Non-Coding Genome
CountryGermany
CityHeidelberg
Period13/10/1016/10/10

Fingerprint

Androgen Receptors
MicroRNAs
Prostatic Neoplasms
3' Untranslated Regions
Androgens
RNA Sequence Analysis
Protein Array Analysis
Proteins
Castration
Regulator Genes

Cite this

Östling, P., Leivonen, S-K., Aakula, A., Kohonen, P., Mäkelä, R., Hagman, Z., ... Kallioniemi, O. (2010). Systematic analysis of microRNAs targeting the androgen receptor in prostate cancer cells. Paper presented at EMBO-EMBL Symposium - The Non-Coding Genome, Heidelberg, Germany.
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. Paper presented at EMBO-EMBL Symposium - The Non-Coding Genome, Heidelberg, Germany.
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title = "Systematic analysis of microRNAs targeting the androgen receptor in prostate cancer cells",
abstract = "Androgen receptor (AR) is expressed in all stages of prostate cancer progression and its levels increase in the castration-resistant tumors. However, the mechanisms regulating AR expression remain poorly understood. Here, our aim was to determine the role of miRNAs in regulating AR protein. To this end, we performed a systematic gain-of function screen for 1129 miRNA molecules in prostate cancer cell lines and quantified changes in AR protein content using protein lysate microarrays. We identified 71 unique miRNAs that influenced the level of AR in LNCaP, LAPC-4, 22Rv1, CWR-1R and MDA-PCa-2B cells. Our RNA-sequencing data showed that the 3'UTRs of many genes, including the AR, are much longer than currently used by target prediction programs. Our analyses predicted that the majority of the miRNA regulation of AR would occur through the extended 6 kb 3'UTR. 3'UTR-binding assays validated 13 miRNAs (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) as direct AR regulators. Fifteen AR down-regulating miRNAs decreased androgen-induced proliferation of prostate cancer cells in vitro. Negative correlation of miR-34a and miR-34c expression with AR levels was also found in clinical prostate cancers. To conclude, our results demonstrate that miRNAs interacting with the long 3'UTR of the AR gene are important regulators of AR protein levels. This could be applied for developing novel therapeutic strategies to inhibit AR function and androgen-dependent cell growth.",
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",
note = "Project code: 35463 Projektin nimi: SA popaivi; EMBO-EMBL Symposium - The Non-Coding Genome ; Conference date: 13-10-2010 Through 16-10-2010",
year = "2010",
language = "English",

}

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 2010, 'Systematic analysis of microRNAs targeting the androgen receptor in prostate cancer cells', Paper presented at EMBO-EMBL Symposium - The Non-Coding Genome, Heidelberg, Germany, 13/10/10 - 16/10/10.

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.

2010. Paper presented at EMBO-EMBL Symposium - The Non-Coding Genome, Heidelberg, Germany.

Research output: Contribution to conferenceConference articleScientific

TY - CONF

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

N1 - Project code: 35463 Projektin nimi: SA popaivi

PY - 2010

Y1 - 2010

N2 - Androgen receptor (AR) is expressed in all stages of prostate cancer progression and its levels increase in the castration-resistant tumors. However, the mechanisms regulating AR expression remain poorly understood. Here, our aim was to determine the role of miRNAs in regulating AR protein. To this end, we performed a systematic gain-of function screen for 1129 miRNA molecules in prostate cancer cell lines and quantified changes in AR protein content using protein lysate microarrays. We identified 71 unique miRNAs that influenced the level of AR in LNCaP, LAPC-4, 22Rv1, CWR-1R and MDA-PCa-2B cells. Our RNA-sequencing data showed that the 3'UTRs of many genes, including the AR, are much longer than currently used by target prediction programs. Our analyses predicted that the majority of the miRNA regulation of AR would occur through the extended 6 kb 3'UTR. 3'UTR-binding assays validated 13 miRNAs (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) as direct AR regulators. Fifteen AR down-regulating miRNAs decreased androgen-induced proliferation of prostate cancer cells in vitro. Negative correlation of miR-34a and miR-34c expression with AR levels was also found in clinical prostate cancers. To conclude, our results demonstrate that miRNAs interacting with the long 3'UTR of the AR gene are important regulators of AR protein levels. This could be applied for developing novel therapeutic strategies to inhibit AR function and androgen-dependent cell growth.

AB - Androgen receptor (AR) is expressed in all stages of prostate cancer progression and its levels increase in the castration-resistant tumors. However, the mechanisms regulating AR expression remain poorly understood. Here, our aim was to determine the role of miRNAs in regulating AR protein. To this end, we performed a systematic gain-of function screen for 1129 miRNA molecules in prostate cancer cell lines and quantified changes in AR protein content using protein lysate microarrays. We identified 71 unique miRNAs that influenced the level of AR in LNCaP, LAPC-4, 22Rv1, CWR-1R and MDA-PCa-2B cells. Our RNA-sequencing data showed that the 3'UTRs of many genes, including the AR, are much longer than currently used by target prediction programs. Our analyses predicted that the majority of the miRNA regulation of AR would occur through the extended 6 kb 3'UTR. 3'UTR-binding assays validated 13 miRNAs (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) as direct AR regulators. Fifteen AR down-regulating miRNAs decreased androgen-induced proliferation of prostate cancer cells in vitro. Negative correlation of miR-34a and miR-34c expression with AR levels was also found in clinical prostate cancers. To conclude, our results demonstrate that miRNAs interacting with the long 3'UTR of the AR gene are important regulators of AR protein levels. This could be applied for developing novel therapeutic strategies to inhibit AR function and androgen-dependent cell growth.

M3 - Conference article

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. 2010. Paper presented at EMBO-EMBL Symposium - The Non-Coding Genome, Heidelberg, Germany.