Androgen receptor-interacting protein HSPBAP1 facilitates growth of prostate cancer cells in androgen-deficient conditions

K. Saeed, P. Östling, M. Björkman, T. Mirtti, K. Alanen, T. Vesterinen, A. Sankila, J. Lundin, M. Lundin, A. Rannikko, S. Nordling, J.-P. Mpindi, P. Kohonen, K. Iljin, O. Kallioniemi (Corresponding Author), Juha K. Rantala

Research output: Contribution to journalArticleScientificpeer-review

5 Citations (Scopus)

Abstract

Hormonal therapies targeting androgen receptor (AR) are effective in prostate cancer (PCa), but often the cancers progress to fatal castrate-resistant disease. Improved understanding of the cellular events during androgen deprivation would help to identify survival and stress pathways whose inhibition could synergize with androgen deprivation. Toward this aim, we performed an RNAi screen on 2,068 genes, including kinases, phosphatases, epigenetic enzymes and other druggable gene targets. High-content cell spot microarray (CSMA) screen was performed in VCaP cells in the presence and absence of androgens with detection of Ki67 and cleaved ADP-ribose polymerase (cPARP) as assays for cell proliferation and apoptosis. Thirty-nine candidate genes were identified, whose silencing inhibited proliferation or induced apoptosis of VCaP cells exclusively under androgen-deprived conditions. One of the candidates, HSPB (heat shock 27 kDa)-associated protein 1 (HSPBAP1), was confirmed to be highly expressed in tumor samples and its mRNA expression levels increased with the Gleason grade. We found that strong HSPBAP1 immunohistochemical staining (IHC) was associated with shorter disease-specific survival of PCa patients compared with negative to moderate staining. Furthermore, we demonstrate that HSPBAP1 interacts with AR in the nucleus of PCa cells specifically during androgen-deprived conditions, occupies chromatin at PSA/klk3 and TMPRSS2/tmprss2 enhancers and regulates their expression. In conclusion, we suggest that HSPBAP1 aids in sustaining cell viability by maintaining AR signaling during androgen-deprived conditions.
Original languageEnglish
Pages (from-to)2535-2545
JournalInternational Journal of Cancer
Volume136
Issue number11
DOIs
Publication statusPublished - 2015
MoE publication typeA1 Journal article-refereed

Fingerprint

Receptor-Interacting Protein Serine-Threonine Kinases
Androgen Receptors
Androgens
Prostatic Neoplasms
Growth
Adenosine Diphosphate Ribose
Apoptosis
Staining and Labeling
Genes
Survival
RNA Interference
Phosphoric Monoester Hydrolases
Epigenomics
Chromatin
Shock
Neoplasms
Cell Survival
Phosphotransferases
Hot Temperature
Cell Proliferation

Keywords

  • prostate cancer
  • HSPBAP1
  • cell spot microarray (CSMA)
  • androgen receptor
  • RNAi sensitization

Cite this

Saeed, K., Östling, P., Björkman, M., Mirtti, T., Alanen, K., Vesterinen, T., ... Rantala, J. K. (2015). Androgen receptor-interacting protein HSPBAP1 facilitates growth of prostate cancer cells in androgen-deficient conditions. International Journal of Cancer, 136(11), 2535-2545. https://doi.org/10.1002/ijc.29303
Saeed, K. ; Östling, P. ; Björkman, M. ; Mirtti, T. ; Alanen, K. ; Vesterinen, T. ; Sankila, A. ; Lundin, J. ; Lundin, M. ; Rannikko, A. ; Nordling, S. ; Mpindi, J.-P. ; Kohonen, P. ; Iljin, K. ; Kallioniemi, O. ; Rantala, Juha K. / Androgen receptor-interacting protein HSPBAP1 facilitates growth of prostate cancer cells in androgen-deficient conditions. In: International Journal of Cancer. 2015 ; Vol. 136, No. 11. pp. 2535-2545.
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title = "Androgen receptor-interacting protein HSPBAP1 facilitates growth of prostate cancer cells in androgen-deficient conditions",
abstract = "Hormonal therapies targeting androgen receptor (AR) are effective in prostate cancer (PCa), but often the cancers progress to fatal castrate-resistant disease. Improved understanding of the cellular events during androgen deprivation would help to identify survival and stress pathways whose inhibition could synergize with androgen deprivation. Toward this aim, we performed an RNAi screen on 2,068 genes, including kinases, phosphatases, epigenetic enzymes and other druggable gene targets. High-content cell spot microarray (CSMA) screen was performed in VCaP cells in the presence and absence of androgens with detection of Ki67 and cleaved ADP-ribose polymerase (cPARP) as assays for cell proliferation and apoptosis. Thirty-nine candidate genes were identified, whose silencing inhibited proliferation or induced apoptosis of VCaP cells exclusively under androgen-deprived conditions. One of the candidates, HSPB (heat shock 27 kDa)-associated protein 1 (HSPBAP1), was confirmed to be highly expressed in tumor samples and its mRNA expression levels increased with the Gleason grade. We found that strong HSPBAP1 immunohistochemical staining (IHC) was associated with shorter disease-specific survival of PCa patients compared with negative to moderate staining. Furthermore, we demonstrate that HSPBAP1 interacts with AR in the nucleus of PCa cells specifically during androgen-deprived conditions, occupies chromatin at PSA/klk3 and TMPRSS2/tmprss2 enhancers and regulates their expression. In conclusion, we suggest that HSPBAP1 aids in sustaining cell viability by maintaining AR signaling during androgen-deprived conditions.",
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author = "K. Saeed and P. {\"O}stling and M. Bj{\"o}rkman and T. Mirtti and K. Alanen and T. Vesterinen and A. Sankila and J. Lundin and M. Lundin and A. Rannikko and S. Nordling and J.-P. Mpindi and P. Kohonen and K. Iljin and O. Kallioniemi and Rantala, {Juha K.}",
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Saeed, K, Östling, P, Björkman, M, Mirtti, T, Alanen, K, Vesterinen, T, Sankila, A, Lundin, J, Lundin, M, Rannikko, A, Nordling, S, Mpindi, J-P, Kohonen, P, Iljin, K, Kallioniemi, O & Rantala, JK 2015, 'Androgen receptor-interacting protein HSPBAP1 facilitates growth of prostate cancer cells in androgen-deficient conditions', International Journal of Cancer, vol. 136, no. 11, pp. 2535-2545. https://doi.org/10.1002/ijc.29303

Androgen receptor-interacting protein HSPBAP1 facilitates growth of prostate cancer cells in androgen-deficient conditions. / Saeed, K.; Östling, P.; Björkman, M.; Mirtti, T.; Alanen, K.; Vesterinen, T.; Sankila, A.; Lundin, J.; Lundin, M.; Rannikko, A.; Nordling, S.; Mpindi, J.-P.; Kohonen, P.; Iljin, K.; Kallioniemi, O. (Corresponding Author); Rantala, Juha K.

In: International Journal of Cancer, Vol. 136, No. 11, 2015, p. 2535-2545.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Androgen receptor-interacting protein HSPBAP1 facilitates growth of prostate cancer cells in androgen-deficient conditions

AU - Saeed, K.

AU - Östling, P.

AU - Björkman, M.

AU - Mirtti, T.

AU - Alanen, K.

AU - Vesterinen, T.

AU - Sankila, A.

AU - Lundin, J.

AU - Lundin, M.

AU - Rannikko, A.

AU - Nordling, S.

AU - Mpindi, J.-P.

AU - Kohonen, P.

AU - Iljin, K.

AU - Kallioniemi, O.

AU - Rantala, Juha K.

PY - 2015

Y1 - 2015

N2 - Hormonal therapies targeting androgen receptor (AR) are effective in prostate cancer (PCa), but often the cancers progress to fatal castrate-resistant disease. Improved understanding of the cellular events during androgen deprivation would help to identify survival and stress pathways whose inhibition could synergize with androgen deprivation. Toward this aim, we performed an RNAi screen on 2,068 genes, including kinases, phosphatases, epigenetic enzymes and other druggable gene targets. High-content cell spot microarray (CSMA) screen was performed in VCaP cells in the presence and absence of androgens with detection of Ki67 and cleaved ADP-ribose polymerase (cPARP) as assays for cell proliferation and apoptosis. Thirty-nine candidate genes were identified, whose silencing inhibited proliferation or induced apoptosis of VCaP cells exclusively under androgen-deprived conditions. One of the candidates, HSPB (heat shock 27 kDa)-associated protein 1 (HSPBAP1), was confirmed to be highly expressed in tumor samples and its mRNA expression levels increased with the Gleason grade. We found that strong HSPBAP1 immunohistochemical staining (IHC) was associated with shorter disease-specific survival of PCa patients compared with negative to moderate staining. Furthermore, we demonstrate that HSPBAP1 interacts with AR in the nucleus of PCa cells specifically during androgen-deprived conditions, occupies chromatin at PSA/klk3 and TMPRSS2/tmprss2 enhancers and regulates their expression. In conclusion, we suggest that HSPBAP1 aids in sustaining cell viability by maintaining AR signaling during androgen-deprived conditions.

AB - Hormonal therapies targeting androgen receptor (AR) are effective in prostate cancer (PCa), but often the cancers progress to fatal castrate-resistant disease. Improved understanding of the cellular events during androgen deprivation would help to identify survival and stress pathways whose inhibition could synergize with androgen deprivation. Toward this aim, we performed an RNAi screen on 2,068 genes, including kinases, phosphatases, epigenetic enzymes and other druggable gene targets. High-content cell spot microarray (CSMA) screen was performed in VCaP cells in the presence and absence of androgens with detection of Ki67 and cleaved ADP-ribose polymerase (cPARP) as assays for cell proliferation and apoptosis. Thirty-nine candidate genes were identified, whose silencing inhibited proliferation or induced apoptosis of VCaP cells exclusively under androgen-deprived conditions. One of the candidates, HSPB (heat shock 27 kDa)-associated protein 1 (HSPBAP1), was confirmed to be highly expressed in tumor samples and its mRNA expression levels increased with the Gleason grade. We found that strong HSPBAP1 immunohistochemical staining (IHC) was associated with shorter disease-specific survival of PCa patients compared with negative to moderate staining. Furthermore, we demonstrate that HSPBAP1 interacts with AR in the nucleus of PCa cells specifically during androgen-deprived conditions, occupies chromatin at PSA/klk3 and TMPRSS2/tmprss2 enhancers and regulates their expression. In conclusion, we suggest that HSPBAP1 aids in sustaining cell viability by maintaining AR signaling during androgen-deprived conditions.

KW - prostate cancer

KW - HSPBAP1

KW - cell spot microarray (CSMA)

KW - androgen receptor

KW - RNAi sensitization

U2 - 10.1002/ijc.29303

DO - 10.1002/ijc.29303

M3 - Article

VL - 136

SP - 2535

EP - 2545

JO - International Journal of Cancer

JF - International Journal of Cancer

SN - 0020-7136

IS - 11

ER -