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

Khalid Saeed, Päivi Kristina Östling, Mari Björkman, Tuomas Mirtti, Kalle Alanen, Tiina Vesterinen, Anna Sankila, Johan Lundin, Mikael Lundin, Antti Rannikko, Stig Nordling, John-Patrick Mpindi, Pekka Kohonen, Kristiina Iljin, Olli Kallioniemi, Juha K. Rantala

Forskningsoutput: TidskriftsbidragArtikelVetenskapligPeer review

Sammanfattning

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.
Originalspråkengelska
TidskriftInternational Journal of Cancer
Volym136
Utgåva11
Sidor (från-till)2535-2545
Antal sidor11
ISSN0020-7136
DOI
StatusPublicerad - 2015
MoE-publikationstypA1 Tidskriftsartikel-refererad

Vetenskapsgrenar

  • 3111 Biomedicinska vetenskaper

Citera det här

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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 tofatal castrate-resistant disease. Improved understanding of the cellular events during androgen deprivation would help toidentify survival and stress pathways whose inhibition could synergize with androgen deprivation. Toward this aim, we performedan 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 androgenswith detection of Ki67 and cleaved ADP-ribose polymerase (cPARP) as assays for cell proliferation and apoptosis. Thirty-ninecandidate genes were identified, whose silencing inhibited proliferation or induced apoptosis of VCaP cells exclusively underandrogen-deprived conditions. One of the candidates, HSPB (heat shock 27 kDa)-associated protein 1 (HSPBAP1), was confirmedto be highly expressed in tumor samples and its mRNA expression levels increased with the Gleason grade. We foundthat strong HSPBAP1 immunohistochemical staining (IHC) was associated with shorter disease-specific survival of PCa patientscompared with negative to moderate staining. Furthermore, we demonstrate that HSPBAP1 interacts with AR in the nucleus ofPCa cells specifically during androgen-deprived conditions, occupies chromatin at PSA/klk3 and TMPRSS2/tmprss2 enhancersand regulates their expression. In conclusion, we suggest that HSPBAP1 aids in sustaining cell viability by maintaining AR signalingduring androgen-deprived conditions.",
keywords = "3111 Biomedicine",
author = "Khalid Saeed and {\"O}stling, {P{\"a}ivi Kristina} and Mari Bj{\"o}rkman and Tuomas Mirtti and Kalle Alanen and Tiina Vesterinen and Anna Sankila and Johan Lundin and Mikael Lundin and Antti Rannikko and Stig Nordling and John-Patrick Mpindi and Pekka Kohonen and Kristiina Iljin and Olli Kallioniemi and Rantala, {Juha K.}",
year = "2015",
doi = "10.1002/ijc.29303",
language = "English",
volume = "136",
pages = "2535--2545",
journal = "International Journal of Cancer",
issn = "0020-7136",
publisher = "Wiley",
number = "11",

}

Androgen receptor-interacting protein HSPBAP1 facilitates growth of prostate cancer cells in androgen-deficient conditions. / Saeed, Khalid; Östling, Päivi Kristina; Björkman, Mari; Mirtti, Tuomas; Alanen, Kalle ; Vesterinen, Tiina; Sankila, Anna; Lundin, Johan; Lundin, Mikael; Rannikko, Antti; Nordling, Stig ; Mpindi, John-Patrick; Kohonen, Pekka; Iljin, Kristiina; Kallioniemi, Olli; Rantala, Juha K.

I: International Journal of Cancer, Vol. 136, Nr. 11, 2015, s. 2535-2545.

Forskningsoutput: TidskriftsbidragArtikelVetenskapligPeer review

TY - JOUR

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

AU - Saeed, Khalid

AU - Östling, Päivi Kristina

AU - Björkman, Mari

AU - Mirtti, Tuomas

AU - Alanen, Kalle

AU - Vesterinen, Tiina

AU - Sankila, Anna

AU - Lundin, Johan

AU - Lundin, Mikael

AU - Rannikko, Antti

AU - Nordling, Stig

AU - Mpindi, John-Patrick

AU - Kohonen, Pekka

AU - Iljin, Kristiina

AU - Kallioniemi, Olli

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 tofatal castrate-resistant disease. Improved understanding of the cellular events during androgen deprivation would help toidentify survival and stress pathways whose inhibition could synergize with androgen deprivation. Toward this aim, we performedan 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 androgenswith detection of Ki67 and cleaved ADP-ribose polymerase (cPARP) as assays for cell proliferation and apoptosis. Thirty-ninecandidate genes were identified, whose silencing inhibited proliferation or induced apoptosis of VCaP cells exclusively underandrogen-deprived conditions. One of the candidates, HSPB (heat shock 27 kDa)-associated protein 1 (HSPBAP1), was confirmedto be highly expressed in tumor samples and its mRNA expression levels increased with the Gleason grade. We foundthat strong HSPBAP1 immunohistochemical staining (IHC) was associated with shorter disease-specific survival of PCa patientscompared with negative to moderate staining. Furthermore, we demonstrate that HSPBAP1 interacts with AR in the nucleus ofPCa cells specifically during androgen-deprived conditions, occupies chromatin at PSA/klk3 and TMPRSS2/tmprss2 enhancersand regulates their expression. In conclusion, we suggest that HSPBAP1 aids in sustaining cell viability by maintaining AR signalingduring androgen-deprived conditions.

AB - Hormonal therapies targeting androgen receptor (AR) are effective in prostate cancer (PCa), but often the cancers progress tofatal castrate-resistant disease. Improved understanding of the cellular events during androgen deprivation would help toidentify survival and stress pathways whose inhibition could synergize with androgen deprivation. Toward this aim, we performedan 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 androgenswith detection of Ki67 and cleaved ADP-ribose polymerase (cPARP) as assays for cell proliferation and apoptosis. Thirty-ninecandidate genes were identified, whose silencing inhibited proliferation or induced apoptosis of VCaP cells exclusively underandrogen-deprived conditions. One of the candidates, HSPB (heat shock 27 kDa)-associated protein 1 (HSPBAP1), was confirmedto be highly expressed in tumor samples and its mRNA expression levels increased with the Gleason grade. We foundthat strong HSPBAP1 immunohistochemical staining (IHC) was associated with shorter disease-specific survival of PCa patientscompared with negative to moderate staining. Furthermore, we demonstrate that HSPBAP1 interacts with AR in the nucleus ofPCa cells specifically during androgen-deprived conditions, occupies chromatin at PSA/klk3 and TMPRSS2/tmprss2 enhancersand regulates their expression. In conclusion, we suggest that HSPBAP1 aids in sustaining cell viability by maintaining AR signalingduring androgen-deprived conditions.

KW - 3111 Biomedicine

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 -