Dual roles of PARP-1 promote cancer growth and progression

Matthew J. Schiewer, Jonathan F. Goodwin, Sumin Han, J. Chad Brenner, Michael A. Augello, Jeffry L. Dean, Fengzhi Liu, Jamie L. Planck, Preethi Ravindranathan, Arul M. Chinnaiyan, Peter McCue, Leonard G. Gomella, Ganesh V. Raj, Adam P. Dicker, Jonathan R. Brody, John M. Pascal, Margaret M. Centenera, Lisa M. Butler, Wayne D. Tilley, Felix Y. Feng & 1 others Karen E. Knudsen

Research output: Contribution to journalArticle

151 Citations (Scopus)

Abstract

PARP-1 is an abundant nuclear enzyme that modifies substrates by poly(ADP-ribose)- ylation. PARP-1 has well-described functions in DNA damage repair and also functions as a context-specific regulator of transcription factors. With multiple models, data show that PARP-1 elicits protumorigenic effects in androgen receptor (AR)-positive prostate cancer cells, in both the presence and absence of genotoxic insult. Mechanistically, PARP-1 is recruited to sites of AR function, therein promoting AR occupancy and AR function. It was further confirmed in genetically defined systems that PARP-1 supports AR transcriptional function, and that in models of advanced prostate cancer, PARP-1 enzymatic activity is enhanced, further linking PARP-1 to AR activity and disease progression. In vivo analyses show that PARP-1 activity is required for AR function in xenograft tumors, as well as tumor cell growth in vivo and generation and maintenance of castration resistance. Finally, in a novel explant system of primary human tumors, targeting PARP-1 potently suppresses tumor cell proliferation. Collectively, these studies identify novel functions of PARP-1 in promoting disease progression, and ultimately suggest that the dual functions of PARP-1 can be targeted in human prostate cancer to suppress tumor growth and progression to castration resistance. SIGNIFICANCE: These studies introduce a paradigm shift with regard to PARP-1 function in human malignancy, and suggest that the dual functions of PARP-1 in DNA damage repair and transcription factor regulation can be leveraged to suppress pathways critical for promalignant phenotypes in prostate cancer cells by modulation of the DNA damage response and hormone signaling pathways. The combined studies highlight the importance of dual PARP-1 function in malignancy and provide the basis for therapeutic targeting.

Original languageEnglish (US)
Pages (from-to)1134-1149
Number of pages16
JournalCancer Discovery
Volume2
Issue number12
DOIs
StatePublished - Dec 2012

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Androgen Receptors
Growth
Prostatic Neoplasms
Neoplasms
DNA Damage
Castration
DNA Repair
Disease Progression
Transcription Factors
Poly Adenosine Diphosphate Ribose
Critical Pathways
Heterografts
Maintenance
Cell Proliferation
Hormones
Phenotype
Enzymes

ASJC Scopus subject areas

  • Oncology

Cite this

Schiewer, M. J., Goodwin, J. F., Han, S., Chad Brenner, J., Augello, M. A., Dean, J. L., ... Knudsen, K. E. (2012). Dual roles of PARP-1 promote cancer growth and progression. Cancer Discovery, 2(12), 1134-1149. https://doi.org/10.1158/2159-8290.CD-12-0120

Dual roles of PARP-1 promote cancer growth and progression. / Schiewer, Matthew J.; Goodwin, Jonathan F.; Han, Sumin; Chad Brenner, J.; Augello, Michael A.; Dean, Jeffry L.; Liu, Fengzhi; Planck, Jamie L.; Ravindranathan, Preethi; Chinnaiyan, Arul M.; McCue, Peter; Gomella, Leonard G.; Raj, Ganesh V.; Dicker, Adam P.; Brody, Jonathan R.; Pascal, John M.; Centenera, Margaret M.; Butler, Lisa M.; Tilley, Wayne D.; Feng, Felix Y.; Knudsen, Karen E.

In: Cancer Discovery, Vol. 2, No. 12, 12.2012, p. 1134-1149.

Research output: Contribution to journalArticle

Schiewer, MJ, Goodwin, JF, Han, S, Chad Brenner, J, Augello, MA, Dean, JL, Liu, F, Planck, JL, Ravindranathan, P, Chinnaiyan, AM, McCue, P, Gomella, LG, Raj, GV, Dicker, AP, Brody, JR, Pascal, JM, Centenera, MM, Butler, LM, Tilley, WD, Feng, FY & Knudsen, KE 2012, 'Dual roles of PARP-1 promote cancer growth and progression', Cancer Discovery, vol. 2, no. 12, pp. 1134-1149. https://doi.org/10.1158/2159-8290.CD-12-0120
Schiewer MJ, Goodwin JF, Han S, Chad Brenner J, Augello MA, Dean JL et al. Dual roles of PARP-1 promote cancer growth and progression. Cancer Discovery. 2012 Dec;2(12):1134-1149. https://doi.org/10.1158/2159-8290.CD-12-0120
Schiewer, Matthew J. ; Goodwin, Jonathan F. ; Han, Sumin ; Chad Brenner, J. ; Augello, Michael A. ; Dean, Jeffry L. ; Liu, Fengzhi ; Planck, Jamie L. ; Ravindranathan, Preethi ; Chinnaiyan, Arul M. ; McCue, Peter ; Gomella, Leonard G. ; Raj, Ganesh V. ; Dicker, Adam P. ; Brody, Jonathan R. ; Pascal, John M. ; Centenera, Margaret M. ; Butler, Lisa M. ; Tilley, Wayne D. ; Feng, Felix Y. ; Knudsen, Karen E. / Dual roles of PARP-1 promote cancer growth and progression. In: Cancer Discovery. 2012 ; Vol. 2, No. 12. pp. 1134-1149.
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