Inflammation-Induced Oxidative Stress Mediates Gene Fusion Formation in Prostate Cancer

Ram S. Mani; Mohammad A. Amin; Xiangyi Li; Shanker Kalyana-Sundaram; Brendan A. Veeneman; Lei Wang; Aparna Ghosh; Adam Aslam; Susmita G. Ramanand; Bradley J. Rabquer; Wataru Kimura; Maxwell Tran; Xuhong Cao; Sameek Roychowdhury; Saravana M. Dhanasekaran; Nallasivam Palanisamy; Hesham A. Sadek; Payal Kapur; Alisa E. Koch; Arul M. Chinnaiyan

doi:10.1016/j.celrep.2016.11.019

Inflammation-Induced Oxidative Stress Mediates Gene Fusion Formation in Prostate Cancer

Ram S. Mani, Mohammad A. Amin, Xiangyi Li, Shanker Kalyana-Sundaram, Brendan A. Veeneman, Lei Wang, Aparna Ghosh, Adam Aslam, Susmita G. Ramanand, Bradley J. Rabquer, Wataru Kimura, Maxwell Tran, Xuhong Cao, Sameek Roychowdhury, Saravana M. Dhanasekaran, Nallasivam Palanisamy, Hesham A. Sadek, Payal Kapur, Alisa E. Koch, Arul M. Chinnaiyan

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59 Scopus citations

Abstract

Approximately 50% of prostate cancers are associated with gene fusions of the androgen-regulated gene TMPRSS2 to the oncogenic erythroblast transformation-specific (ETS) transcription factor ERG. The three-dimensional proximity of TMPRSS2 and ERG genes, in combination with DNA breaks, facilitates the formation of TMPRSS2-ERG gene fusions. However, the origins of DNA breaks that underlie gene fusion formation in prostate cancers are far from clear. We demonstrate a role for inflammation-induced oxidative stress in the formation of DNA breaks leading to recurrent TMPRSS2-ERG gene fusions. The transcriptional status and epigenetic features of the target genes influence this effect. Importantly, inflammation-induced de novo genomic rearrangements are blocked by homologous recombination (HR) and promoted by non-homologous end-joining (NHEJ) pathways. In conjunction with the association of proliferative inflammatory atrophy (PIA) with human prostate cancer, our results support a working model in which recurrent genomic rearrangements induced by inflammatory stimuli lead to the development of prostate cancer.

Original language	English (US)
Pages (from-to)	2620-2631
Number of pages	12
Journal	Cell Reports
Volume	17
Issue number	10
DOIs	https://doi.org/10.1016/j.celrep.2016.11.019
State	Published - Dec 6 2016

Keywords

DNA breaks
NHEJ
ROS
TMPRSS2-ERG
TNF
gene fusion
inflammation
microhomology
oxidative stress
prostate cancer

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

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10.1016/j.celrep.2016.11.019

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Mani, R. S., Amin, M. A., Li, X., Kalyana-Sundaram, S., Veeneman, B. A., Wang, L., Ghosh, A., Aslam, A., Ramanand, S. G., Rabquer, B. J., Kimura, W., Tran, M., Cao, X., Roychowdhury, S., Dhanasekaran, S. M., Palanisamy, N., Sadek, H. A., Kapur, P., Koch, A. E., & Chinnaiyan, A. M. (2016). Inflammation-Induced Oxidative Stress Mediates Gene Fusion Formation in Prostate Cancer. Cell Reports, 17(10), 2620-2631. https://doi.org/10.1016/j.celrep.2016.11.019

Mani, RS, Amin, MA, Li, X, Kalyana-Sundaram, S, Veeneman, BA, Wang, L, Ghosh, A, Aslam, A, Ramanand, SG, Rabquer, BJ, Kimura, W, Tran, M, Cao, X, Roychowdhury, S, Dhanasekaran, SM, Palanisamy, N, Sadek, HA , Kapur, P, Koch, AE & Chinnaiyan, AM 2016, 'Inflammation-Induced Oxidative Stress Mediates Gene Fusion Formation in Prostate Cancer', Cell Reports, vol. 17, no. 10, pp. 2620-2631. https://doi.org/10.1016/j.celrep.2016.11.019

@article{8e242d47c4d44bdea0401ca43ae8f73e,

title = "Inflammation-Induced Oxidative Stress Mediates Gene Fusion Formation in Prostate Cancer",

abstract = "Approximately 50% of prostate cancers are associated with gene fusions of the androgen-regulated gene TMPRSS2 to the oncogenic erythroblast transformation-specific (ETS) transcription factor ERG. The three-dimensional proximity of TMPRSS2 and ERG genes, in combination with DNA breaks, facilitates the formation of TMPRSS2-ERG gene fusions. However, the origins of DNA breaks that underlie gene fusion formation in prostate cancers are far from clear. We demonstrate a role for inflammation-induced oxidative stress in the formation of DNA breaks leading to recurrent TMPRSS2-ERG gene fusions. The transcriptional status and epigenetic features of the target genes influence this effect. Importantly, inflammation-induced de novo genomic rearrangements are blocked by homologous recombination (HR) and promoted by non-homologous end-joining (NHEJ) pathways. In conjunction with the association of proliferative inflammatory atrophy (PIA) with human prostate cancer, our results support a working model in which recurrent genomic rearrangements induced by inflammatory stimuli lead to the development of prostate cancer.",

keywords = "DNA breaks, NHEJ, ROS, TMPRSS2-ERG, TNF, gene fusion, inflammation, microhomology, oxidative stress, prostate cancer",

author = "Mani, {Ram S.} and Amin, {Mohammad A.} and Xiangyi Li and Shanker Kalyana-Sundaram and Veeneman, {Brendan A.} and Lei Wang and Aparna Ghosh and Adam Aslam and Ramanand, {Susmita G.} and Rabquer, {Bradley J.} and Wataru Kimura and Maxwell Tran and Xuhong Cao and Sameek Roychowdhury and Dhanasekaran, {Saravana M.} and Nallasivam Palanisamy and Sadek, {Hesham A.} and Payal Kapur and Koch, {Alisa E.} and Chinnaiyan, {Arul M.}",

note = "Funding Information: We thank D. Robinson, Y. Wu, and J. Pan for assistance with custom capture sequencing and S. Carskadon for technical assistance. NIH Pathway to Independence (PI) Award R00CA160640 to R.S.M. and startup funds from UT Southwestern supported research reported in this publication. R.S.M. also acknowledges funding from the ACS-IRG New Investigator Award in Cancer Research (IRG-02-196) and the Stewart Rahr-Prostate Cancer Foundation Young Investigator Award. This work was supported in part by NIH Prostate SPORE (P50CA186786), the Early Detection Research Network (U01 CA111275 and R01CA132874), and the Prostate Cancer Foundation. A.M.C. is an American Cancer Society research professor and an A. Alfred Taubman scholar. Publisher Copyright: {\textcopyright} 2016 The Author(s)",

year = "2016",

month = dec,

day = "6",

doi = "10.1016/j.celrep.2016.11.019",

language = "English (US)",

volume = "17",

pages = "2620--2631",

journal = "Cell Reports",

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number = "10",

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T1 - Inflammation-Induced Oxidative Stress Mediates Gene Fusion Formation in Prostate Cancer

AU - Mani, Ram S.

AU - Amin, Mohammad A.

AU - Li, Xiangyi

AU - Kalyana-Sundaram, Shanker

AU - Veeneman, Brendan A.

AU - Wang, Lei

AU - Ghosh, Aparna

AU - Aslam, Adam

AU - Ramanand, Susmita G.

AU - Rabquer, Bradley J.

AU - Kimura, Wataru

AU - Tran, Maxwell

AU - Cao, Xuhong

AU - Roychowdhury, Sameek

AU - Dhanasekaran, Saravana M.

AU - Palanisamy, Nallasivam

AU - Sadek, Hesham A.

AU - Kapur, Payal

AU - Koch, Alisa E.

AU - Chinnaiyan, Arul M.

N1 - Funding Information: We thank D. Robinson, Y. Wu, and J. Pan for assistance with custom capture sequencing and S. Carskadon for technical assistance. NIH Pathway to Independence (PI) Award R00CA160640 to R.S.M. and startup funds from UT Southwestern supported research reported in this publication. R.S.M. also acknowledges funding from the ACS-IRG New Investigator Award in Cancer Research (IRG-02-196) and the Stewart Rahr-Prostate Cancer Foundation Young Investigator Award. This work was supported in part by NIH Prostate SPORE (P50CA186786), the Early Detection Research Network (U01 CA111275 and R01CA132874), and the Prostate Cancer Foundation. A.M.C. is an American Cancer Society research professor and an A. Alfred Taubman scholar. Publisher Copyright: © 2016 The Author(s)

PY - 2016/12/6

Y1 - 2016/12/6

N2 - Approximately 50% of prostate cancers are associated with gene fusions of the androgen-regulated gene TMPRSS2 to the oncogenic erythroblast transformation-specific (ETS) transcription factor ERG. The three-dimensional proximity of TMPRSS2 and ERG genes, in combination with DNA breaks, facilitates the formation of TMPRSS2-ERG gene fusions. However, the origins of DNA breaks that underlie gene fusion formation in prostate cancers are far from clear. We demonstrate a role for inflammation-induced oxidative stress in the formation of DNA breaks leading to recurrent TMPRSS2-ERG gene fusions. The transcriptional status and epigenetic features of the target genes influence this effect. Importantly, inflammation-induced de novo genomic rearrangements are blocked by homologous recombination (HR) and promoted by non-homologous end-joining (NHEJ) pathways. In conjunction with the association of proliferative inflammatory atrophy (PIA) with human prostate cancer, our results support a working model in which recurrent genomic rearrangements induced by inflammatory stimuli lead to the development of prostate cancer.

AB - Approximately 50% of prostate cancers are associated with gene fusions of the androgen-regulated gene TMPRSS2 to the oncogenic erythroblast transformation-specific (ETS) transcription factor ERG. The three-dimensional proximity of TMPRSS2 and ERG genes, in combination with DNA breaks, facilitates the formation of TMPRSS2-ERG gene fusions. However, the origins of DNA breaks that underlie gene fusion formation in prostate cancers are far from clear. We demonstrate a role for inflammation-induced oxidative stress in the formation of DNA breaks leading to recurrent TMPRSS2-ERG gene fusions. The transcriptional status and epigenetic features of the target genes influence this effect. Importantly, inflammation-induced de novo genomic rearrangements are blocked by homologous recombination (HR) and promoted by non-homologous end-joining (NHEJ) pathways. In conjunction with the association of proliferative inflammatory atrophy (PIA) with human prostate cancer, our results support a working model in which recurrent genomic rearrangements induced by inflammatory stimuli lead to the development of prostate cancer.

KW - DNA breaks

KW - NHEJ

KW - ROS

KW - TMPRSS2-ERG

KW - TNF

KW - gene fusion

KW - inflammation

KW - microhomology

KW - oxidative stress

KW - prostate cancer

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DO - 10.1016/j.celrep.2016.11.019

M3 - Article

C2 - 27926866

AN - SCOPUS:85002733481

SN - 2211-1247

VL - 17

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EP - 2631

JO - Cell Reports

JF - Cell Reports

IS - 10

ER -

Inflammation-Induced Oxidative Stress Mediates Gene Fusion Formation in Prostate Cancer

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