Loss of CHD1 Promotes Heterogeneous Mechanisms of Resistance to AR-Targeted Therapy via Chromatin Dysregulation

Zeda Zhang; Chuanli Zhou; Xiaoling Li; Spencer D. Barnes; Su Deng; Elizabeth Hoover; Chi Chao Chen; Young Sun Lee; Yanxiao Zhang; Choushi Wang; Lauren A. Metang; Chao Wu; Carla Rodriguez Tirado; Nickolas A. Johnson; John Wongvipat; Kristina Navrazhina; Zhen Cao; Danielle Choi; Chun Hao Huang; Eliot Linton; Xiaoping Chen; Yupu Liang; Christopher E. Mason; Elisa de Stanchina; Wassim Abida; Amaia Lujambio; Sheng Li; Scott W. Lowe; Joshua T. Mendell; Venkat S. Malladi; Charles L. Sawyers; Ping Mu

doi:10.1016/j.ccell.2020.03.001

Loss of CHD1 Promotes Heterogeneous Mechanisms of Resistance to AR-Targeted Therapy via Chromatin Dysregulation

Zeda Zhang, Chuanli Zhou, Xiaoling Li, Spencer D. Barnes, Su Deng, Elizabeth Hoover, Chi Chao Chen, Young Sun Lee, Yanxiao Zhang, Choushi Wang, Lauren A. Metang, Chao Wu, Carla Rodriguez Tirado, Nickolas A. Johnson, John Wongvipat, Kristina Navrazhina, Zhen Cao, Danielle Choi, Chun Hao Huang, Eliot LintonXiaoping Chen, Yupu Liang, Christopher E. Mason, Elisa de Stanchina, Wassim Abida, Amaia Lujambio, Sheng Li, Scott W. Lowe, Joshua T. Mendell, Venkat S. Malladi, Charles L. Sawyers, Ping Mu

Research output: Contribution to journal › Article › peer-review

8 Scopus citations

Abstract

Metastatic prostate cancer is characterized by recurrent genomic copy number alterations that are presumed to contribute to resistance to hormone therapy. We identified CHD1 loss as a cause of antiandrogen resistance in an in vivo small hairpin RNA (shRNA) screen of 730 genes deleted in prostate cancer. ATAC-seq and RNA-seq analyses showed that CHD1 loss resulted in global changes in open and closed chromatin with associated transcriptomic changes. Integrative analysis of this data, together with CRISPR-based functional screening, identified four transcription factors (NR3C1, POU3F2, NR2F1, and TBX2) that contribute to antiandrogen resistance, with associated activation of non-luminal lineage programs. Thus, CHD1 loss results in chromatin dysregulation, thereby establishing a state of transcriptional plasticity that enables the emergence of antiandrogen resistance through heterogeneous mechanisms.

Original language	English (US)
Pages (from-to)	584-598.e11
Journal	Cancer Cell
Volume	37
Issue number	4
DOIs	https://doi.org/10.1016/j.ccell.2020.03.001
State	Published - Apr 13 2020

Keywords

CHD1
NR2F1
NR3C1 (GR)
POU3F2 (BRN2)
TBX2
antiandrogen resistantce
castration-resistant prostate cancer
chromatin remodeling
lineage plasticity
tumor heterogeneity

ASJC Scopus subject areas

Oncology
Cell Biology
Cancer Research

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Zhang, Z., Zhou, C., Li, X., Barnes, S. D., Deng, S., Hoover, E., Chen, C. C., Lee, Y. S., Zhang, Y., Wang, C., Metang, L. A., Wu, C., Tirado, C. R., Johnson, N. A., Wongvipat, J., Navrazhina, K., Cao, Z., Choi, D., Huang, C. H., ... Mu, P. (2020). Loss of CHD1 Promotes Heterogeneous Mechanisms of Resistance to AR-Targeted Therapy via Chromatin Dysregulation. Cancer Cell, 37(4), 584-598.e11. https://doi.org/10.1016/j.ccell.2020.03.001

Loss of CHD1 Promotes Heterogeneous Mechanisms of Resistance to AR-Targeted Therapy via Chromatin Dysregulation. / Zhang, Zeda; Zhou, Chuanli; Li, Xiaoling; Barnes, Spencer D.; Deng, Su; Hoover, Elizabeth; Chen, Chi Chao; Lee, Young Sun; Zhang, Yanxiao; Wang, Choushi; Metang, Lauren A.; Wu, Chao; Tirado, Carla Rodriguez; Johnson, Nickolas A.; Wongvipat, John; Navrazhina, Kristina; Cao, Zhen; Choi, Danielle; Huang, Chun Hao; Linton, Eliot; Chen, Xiaoping; Liang, Yupu; Mason, Christopher E.; de Stanchina, Elisa; Abida, Wassim; Lujambio, Amaia; Li, Sheng; Lowe, Scott W.; Mendell, Joshua T.; Malladi, Venkat S.; Sawyers, Charles L.; Mu, Ping.

In: Cancer Cell, Vol. 37, No. 4, 13.04.2020, p. 584-598.e11.

Research output: Contribution to journal › Article › peer-review

Zhang, Z, Zhou, C, Li, X, Barnes, SD, Deng, S, Hoover, E, Chen, CC, Lee, YS, Zhang, Y, Wang, C, Metang, LA, Wu, C, Tirado, CR, Johnson, NA, Wongvipat, J, Navrazhina, K, Cao, Z, Choi, D, Huang, CH, Linton, E, Chen, X, Liang, Y, Mason, CE, de Stanchina, E, Abida, W, Lujambio, A, Li, S, Lowe, SW, Mendell, JT , Malladi, VS, Sawyers, CL & Mu, P 2020, 'Loss of CHD1 Promotes Heterogeneous Mechanisms of Resistance to AR-Targeted Therapy via Chromatin Dysregulation', Cancer Cell, vol. 37, no. 4, pp. 584-598.e11. https://doi.org/10.1016/j.ccell.2020.03.001

Zhang, Zeda ; Zhou, Chuanli ; Li, Xiaoling ; Barnes, Spencer D. ; Deng, Su ; Hoover, Elizabeth ; Chen, Chi Chao ; Lee, Young Sun ; Zhang, Yanxiao ; Wang, Choushi ; Metang, Lauren A. ; Wu, Chao ; Tirado, Carla Rodriguez ; Johnson, Nickolas A. ; Wongvipat, John ; Navrazhina, Kristina ; Cao, Zhen ; Choi, Danielle ; Huang, Chun Hao ; Linton, Eliot ; Chen, Xiaoping ; Liang, Yupu ; Mason, Christopher E. ; de Stanchina, Elisa ; Abida, Wassim ; Lujambio, Amaia ; Li, Sheng ; Lowe, Scott W. ; Mendell, Joshua T. ; Malladi, Venkat S. ; Sawyers, Charles L. ; Mu, Ping. / Loss of CHD1 Promotes Heterogeneous Mechanisms of Resistance to AR-Targeted Therapy via Chromatin Dysregulation. In: Cancer Cell. 2020 ; Vol. 37, No. 4. pp. 584-598.e11.

@article{dfe4a38ccd2d4673bc316210c1f4d671,

title = "Loss of CHD1 Promotes Heterogeneous Mechanisms of Resistance to AR-Targeted Therapy via Chromatin Dysregulation",

abstract = "Metastatic prostate cancer is characterized by recurrent genomic copy number alterations that are presumed to contribute to resistance to hormone therapy. We identified CHD1 loss as a cause of antiandrogen resistance in an in vivo small hairpin RNA (shRNA) screen of 730 genes deleted in prostate cancer. ATAC-seq and RNA-seq analyses showed that CHD1 loss resulted in global changes in open and closed chromatin with associated transcriptomic changes. Integrative analysis of this data, together with CRISPR-based functional screening, identified four transcription factors (NR3C1, POU3F2, NR2F1, and TBX2) that contribute to antiandrogen resistance, with associated activation of non-luminal lineage programs. Thus, CHD1 loss results in chromatin dysregulation, thereby establishing a state of transcriptional plasticity that enables the emergence of antiandrogen resistance through heterogeneous mechanisms.",

keywords = "CHD1, NR2F1, NR3C1 (GR), POU3F2 (BRN2), TBX2, antiandrogen resistantce, castration-resistant prostate cancer, chromatin remodeling, lineage plasticity, tumor heterogeneity",

author = "Zeda Zhang and Chuanli Zhou and Xiaoling Li and Barnes, {Spencer D.} and Su Deng and Elizabeth Hoover and Chen, {Chi Chao} and Lee, {Young Sun} and Yanxiao Zhang and Choushi Wang and Metang, {Lauren A.} and Chao Wu and Tirado, {Carla Rodriguez} and Johnson, {Nickolas A.} and John Wongvipat and Kristina Navrazhina and Zhen Cao and Danielle Choi and Huang, {Chun Hao} and Eliot Linton and Xiaoping Chen and Yupu Liang and Mason, {Christopher E.} and {de Stanchina}, Elisa and Wassim Abida and Amaia Lujambio and Sheng Li and Lowe, {Scott W.} and Mendell, {Joshua T.} and Malladi, {Venkat S.} and Sawyers, {Charles L.} and Ping Mu",

note = "Funding Information: We thank the cBioPortal, SU2C, and TCGA for providing genomic and transcriptomic data. We thank A.Viale, N. Socci, D. Nabors, and the MSKCC Integrated Genomics Operation for assistance with the library HiSeq. We thank A. Heguy and the NYU Genome Technology Center for assistance with the RNA-seq and ATAC-seq. We thank J. Zuber for providing retroviral- and lentiviral miR-E-based expression vectors, P. Chi and E. Wong for providing CHD1-expressing vectors, E. Lee, D.P. Yun, and H.A. Chen for providing constructs, W. Wu for all the artwork. We thank G. Hannon for critical discussion and feedback. This work was supported or partially supported by: the National Cancer Institute (NCI) and National Institutes of Health (NIH), USA (R00CA218885-04 to P.M. R01CA155169?04 and R01CA19387-01 to C.L.S. F99CA223063 to Z.Z. P30CA008748 to E.d.S. U54OD020355 to S.W.L. and E.d.S. P30CA034196 to S.L. R35CA197311 to J.T.M. and 1R01MH117406 to C.E.M.), Department of Defense, USA (PC170900 to P.M.), Cancer Prevention Research Institute (CPRIT), USA (RR170050 to P.M. RP160249 to J.T.M. and RP150596 to S.B. and V.M.), Prostate Cancer Foundation, USA (17YOUN12 to P.M.), Welch Foundation, USA (I-2005-20190330 to P.M. and I-1961-20180324 to J.T.M.), UTSW Deborah and W.A. Tex Moncrief, Jr. Scholar in Medical Research Award, USA (to P.M.), UTSW Harold C. Simmons Cancer Center Pilot Award, USA (to P.M.), Howard Hughes Medical Institute, USA (DT0712 to C.L.S. J.T.M. and S.L.W.), NIH/NCI/MSKCC Spore in Prostate Cancer, USA (P50 CA092629-14 to C.L.S.), NCI/MSKCC Support Grant/Core Grant, USA (P30CA008748-49 and P3CA008748-49-S2 to C.L.S.), the Starr Cancer Consortium, USA (I9-A9-071 to C.E.M.), the Vallee Foundation, USA (to C.E.M.), the WorldQuant Foundation, USA (to C.E.M.), the Pershing Square Sohn Cancer Research Alliance, USA (to C.E.M.), the Leukemia and Lymphoma Society, USA (LLS 9238-16 and LLS-MCL-982 to C.E.M.), the Jackson Laboratory New Investigator Award, USA (to S.L.), the Director's Innovation Fund, USA (to S.L.), and the NCATS (UL1 TR001866 to Y.L.). C.L.S. and P.M. conceived the project. Z.Z. C.Z. X.L. P.M. and C.L.S. oversaw the project, designed experiments, and interpreted data. P.M. and C.L.S. co-wrote the manuscript. K.N. and L.M. edited the manuscript. P.M. S.L. Y.L. and C.E.M. established the deletome. A.L. designed the shRNA library. E.H. Z.C. and C.-H.H. constructed the shRNA library. Z.Z. C.Z. X.L. E.H. S.D. K.N. Y.S.L. C.W. and N.J. cloned all other plasmid constructs. Z.Z. X.L. N.J. J.W. D.C. X.C. and E.d.S. performed in vivo experiments. C.-C.C. S.B. V.M. J.T.M. and P.M. analyzed the library results. S.B. V.M. C.-C.C. and P.M. performed bioinformatic analysis. Z.Z. C.Z. X.L. S.D. C.R.T. and L.M. performed competition assays. Z.Z. C.Z. X.L. and S.D. established the tumor-derived cell lines. X.L. and S.D. performed inducible shCHD1 and CHD1 rescue experiments. X.L. performed immunofluorescence and immunohistochemistry. X.L. S.D. C.W. and C.R.T. performed dose-response experiments. S.D. performed proliferation assays. C.Z. X.L. and C.W. performed the CRISPR library screen. Z.Z. C.Z. X.L. S.D. E.H. and C.W. performed western blots and qPCR. W.A. Y.Z. Z.Z. E.L. and P.M. performed clinical data analysis. Y.Z. examined all the statistic tests. S.W.L. supervised the construction of the library and offered critical feedback. C.L.S. and P.M. are the corresponding authors of this manuscript. C.L.S. and J.W. are co-inventors of enzalutamide and apalutamide and may be entitled to royalties. C.L.S. serves on the Board of Directors of Novartis and is a co-founder of ORIC Pharm. He is a science advisor to Agios, Beigene, Blueprint, Column Group, Foghorn, Housey Pharma, Nextech, KSQ, Petra, and PMV. He was a co-founder of Seragon, purchased by Genentech/Roche in 2014. S.W.L. is a founder and member of the scientific advisory board of ORIC Pharmaceuticals, Blueprint Medicines, and Mirimus, Inc.; he is also on the scientific advisory board of PMV Pharmaceuticals, Constellation Pharmaceuticals, and Petra Pharmaceuticals. W.A. reports consulting for Clovis Oncology, Janssen, MORE Health, and ORIC Pharmaceuticals. He received honoraria from CARET and travel accommodations from GlaxoSmith Kline, Clovis Oncology, and ORIC Pharmaceuticals. C.E.M is a co-founder and board member for Biotia and Onegevity Health, as well as an advisor for Genpro and Karius. Funding Information: We thank the cBioPortal, SU2C, and TCGA for providing genomic and transcriptomic data. We thank A.Viale, N. Socci, D. Nabors, and the MSKCC Integrated Genomics Operation for assistance with the library HiSeq. We thank A. Heguy and the NYU Genome Technology Center for assistance with the RNA-seq and ATAC-seq. We thank J. Zuber for providing retroviral- and lentiviral miR-E-based expression vectors, P. Chi and E. Wong for providing CHD1 -expressing vectors, E. Lee, D.P. Yun, and H.A. Chen for providing constructs, W. Wu for all the artwork. We thank G. Hannon for critical discussion and feedback. This work was supported or partially supported by: the National Cancer Institute (NCI) and National Institutes of Health (NIH) , USA ( R00CA218885-04 to P.M., R01CA155169–04 and R01CA19387-01 to C.L.S., F99CA223063 to Z.Z., P30CA008748 to E.d.S., U54OD020355 to S.W.L. and E.d.S., P30CA034196 to S.L., R35CA197311 to J.T.M., and 1R01MH117406 to C.E.M.), Department of Defense, USA ( PC170900 to P.M.), Cancer Prevention Research Institute (CPRIT), USA ( RR170050 to P.M., RP160249 to J.T.M., and RP150596 to S.B. and V.M.), Prostate Cancer Foundation, USA ( 17YOUN12 to P.M.), Welch Foundation, USA ( I-2005-20190330 to P.M. and I-1961-20180324 to J.T.M.), UTSW Deborah and W.A. Tex Moncrief, Jr. Scholar in Medical Research Award, USA (to P.M.), UTSW Harold C. Simmons Cancer Center Pilot Award, USA (to P.M.), Howard Hughes Medical Institute, USA ( DT0712 to C.L.S., J.T.M., and S.L.W.), NIH /NCI/MSKCC Spore in Prostate Cancer, USA ( P50 CA092629-14 to C.L.S.), NCI /MSKCC Support Grant/Core Grant, USA ( P30CA008748-49 and P3CA008748-49-S2 to C.L.S.), the Starr Cancer Consortium, USA (I9-A9-071 to C.E.M.), the Vallee Foundation, USA (to C.E.M.), the WorldQuant Foundation, USA (to C.E.M.), the Pershing Square Sohn Cancer Research Alliance, USA (to C.E.M.), the Leukemia and Lymphoma Society, USA ( LLS 9238-16 and LLS-MCL-982 to C.E.M.), the Jackson Laboratory New Investigator Award, USA (to S.L.), the Director{\textquoteright}s Innovation Fund, USA (to S.L.), and the NCATS ( UL1 TR001866 to Y.L.). ",

year = "2020",

month = apr,

day = "13",

doi = "10.1016/j.ccell.2020.03.001",

language = "English (US)",

volume = "37",

pages = "584--598.e11",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "4",

}

TY - JOUR

T1 - Loss of CHD1 Promotes Heterogeneous Mechanisms of Resistance to AR-Targeted Therapy via Chromatin Dysregulation

AU - Zhang, Zeda

AU - Zhou, Chuanli

AU - Li, Xiaoling

AU - Barnes, Spencer D.

AU - Deng, Su

AU - Hoover, Elizabeth

AU - Chen, Chi Chao

AU - Lee, Young Sun

AU - Zhang, Yanxiao

AU - Wang, Choushi

AU - Metang, Lauren A.

AU - Wu, Chao

AU - Tirado, Carla Rodriguez

AU - Johnson, Nickolas A.

AU - Wongvipat, John

AU - Navrazhina, Kristina

AU - Cao, Zhen

AU - Choi, Danielle

AU - Huang, Chun Hao

AU - Linton, Eliot

AU - Chen, Xiaoping

AU - Liang, Yupu

AU - Mason, Christopher E.

AU - de Stanchina, Elisa

AU - Abida, Wassim

AU - Lujambio, Amaia

AU - Li, Sheng

AU - Lowe, Scott W.

AU - Mendell, Joshua T.

AU - Malladi, Venkat S.

AU - Sawyers, Charles L.

AU - Mu, Ping

N1 - Funding Information: We thank the cBioPortal, SU2C, and TCGA for providing genomic and transcriptomic data. We thank A.Viale, N. Socci, D. Nabors, and the MSKCC Integrated Genomics Operation for assistance with the library HiSeq. We thank A. Heguy and the NYU Genome Technology Center for assistance with the RNA-seq and ATAC-seq. We thank J. Zuber for providing retroviral- and lentiviral miR-E-based expression vectors, P. Chi and E. Wong for providing CHD1-expressing vectors, E. Lee, D.P. Yun, and H.A. Chen for providing constructs, W. Wu for all the artwork. We thank G. Hannon for critical discussion and feedback. This work was supported or partially supported by: the National Cancer Institute (NCI) and National Institutes of Health (NIH), USA (R00CA218885-04 to P.M. R01CA155169?04 and R01CA19387-01 to C.L.S. F99CA223063 to Z.Z. P30CA008748 to E.d.S. U54OD020355 to S.W.L. and E.d.S. P30CA034196 to S.L. R35CA197311 to J.T.M. and 1R01MH117406 to C.E.M.), Department of Defense, USA (PC170900 to P.M.), Cancer Prevention Research Institute (CPRIT), USA (RR170050 to P.M. RP160249 to J.T.M. and RP150596 to S.B. and V.M.), Prostate Cancer Foundation, USA (17YOUN12 to P.M.), Welch Foundation, USA (I-2005-20190330 to P.M. and I-1961-20180324 to J.T.M.), UTSW Deborah and W.A. Tex Moncrief, Jr. Scholar in Medical Research Award, USA (to P.M.), UTSW Harold C. Simmons Cancer Center Pilot Award, USA (to P.M.), Howard Hughes Medical Institute, USA (DT0712 to C.L.S. J.T.M. and S.L.W.), NIH/NCI/MSKCC Spore in Prostate Cancer, USA (P50 CA092629-14 to C.L.S.), NCI/MSKCC Support Grant/Core Grant, USA (P30CA008748-49 and P3CA008748-49-S2 to C.L.S.), the Starr Cancer Consortium, USA (I9-A9-071 to C.E.M.), the Vallee Foundation, USA (to C.E.M.), the WorldQuant Foundation, USA (to C.E.M.), the Pershing Square Sohn Cancer Research Alliance, USA (to C.E.M.), the Leukemia and Lymphoma Society, USA (LLS 9238-16 and LLS-MCL-982 to C.E.M.), the Jackson Laboratory New Investigator Award, USA (to S.L.), the Director's Innovation Fund, USA (to S.L.), and the NCATS (UL1 TR001866 to Y.L.). C.L.S. and P.M. conceived the project. Z.Z. C.Z. X.L. P.M. and C.L.S. oversaw the project, designed experiments, and interpreted data. P.M. and C.L.S. co-wrote the manuscript. K.N. and L.M. edited the manuscript. P.M. S.L. Y.L. and C.E.M. established the deletome. A.L. designed the shRNA library. E.H. Z.C. and C.-H.H. constructed the shRNA library. Z.Z. C.Z. X.L. E.H. S.D. K.N. Y.S.L. C.W. and N.J. cloned all other plasmid constructs. Z.Z. X.L. N.J. J.W. D.C. X.C. and E.d.S. performed in vivo experiments. C.-C.C. S.B. V.M. J.T.M. and P.M. analyzed the library results. S.B. V.M. C.-C.C. and P.M. performed bioinformatic analysis. Z.Z. C.Z. X.L. S.D. C.R.T. and L.M. performed competition assays. Z.Z. C.Z. X.L. and S.D. established the tumor-derived cell lines. X.L. and S.D. performed inducible shCHD1 and CHD1 rescue experiments. X.L. performed immunofluorescence and immunohistochemistry. X.L. S.D. C.W. and C.R.T. performed dose-response experiments. S.D. performed proliferation assays. C.Z. X.L. and C.W. performed the CRISPR library screen. Z.Z. C.Z. X.L. S.D. E.H. and C.W. performed western blots and qPCR. W.A. Y.Z. Z.Z. E.L. and P.M. performed clinical data analysis. Y.Z. examined all the statistic tests. S.W.L. supervised the construction of the library and offered critical feedback. C.L.S. and P.M. are the corresponding authors of this manuscript. C.L.S. and J.W. are co-inventors of enzalutamide and apalutamide and may be entitled to royalties. C.L.S. serves on the Board of Directors of Novartis and is a co-founder of ORIC Pharm. He is a science advisor to Agios, Beigene, Blueprint, Column Group, Foghorn, Housey Pharma, Nextech, KSQ, Petra, and PMV. He was a co-founder of Seragon, purchased by Genentech/Roche in 2014. S.W.L. is a founder and member of the scientific advisory board of ORIC Pharmaceuticals, Blueprint Medicines, and Mirimus, Inc.; he is also on the scientific advisory board of PMV Pharmaceuticals, Constellation Pharmaceuticals, and Petra Pharmaceuticals. W.A. reports consulting for Clovis Oncology, Janssen, MORE Health, and ORIC Pharmaceuticals. He received honoraria from CARET and travel accommodations from GlaxoSmith Kline, Clovis Oncology, and ORIC Pharmaceuticals. C.E.M is a co-founder and board member for Biotia and Onegevity Health, as well as an advisor for Genpro and Karius. Funding Information: We thank the cBioPortal, SU2C, and TCGA for providing genomic and transcriptomic data. We thank A.Viale, N. Socci, D. Nabors, and the MSKCC Integrated Genomics Operation for assistance with the library HiSeq. We thank A. Heguy and the NYU Genome Technology Center for assistance with the RNA-seq and ATAC-seq. We thank J. Zuber for providing retroviral- and lentiviral miR-E-based expression vectors, P. Chi and E. Wong for providing CHD1 -expressing vectors, E. Lee, D.P. Yun, and H.A. Chen for providing constructs, W. Wu for all the artwork. We thank G. Hannon for critical discussion and feedback. This work was supported or partially supported by: the National Cancer Institute (NCI) and National Institutes of Health (NIH) , USA ( R00CA218885-04 to P.M., R01CA155169–04 and R01CA19387-01 to C.L.S., F99CA223063 to Z.Z., P30CA008748 to E.d.S., U54OD020355 to S.W.L. and E.d.S., P30CA034196 to S.L., R35CA197311 to J.T.M., and 1R01MH117406 to C.E.M.), Department of Defense, USA ( PC170900 to P.M.), Cancer Prevention Research Institute (CPRIT), USA ( RR170050 to P.M., RP160249 to J.T.M., and RP150596 to S.B. and V.M.), Prostate Cancer Foundation, USA ( 17YOUN12 to P.M.), Welch Foundation, USA ( I-2005-20190330 to P.M. and I-1961-20180324 to J.T.M.), UTSW Deborah and W.A. Tex Moncrief, Jr. Scholar in Medical Research Award, USA (to P.M.), UTSW Harold C. Simmons Cancer Center Pilot Award, USA (to P.M.), Howard Hughes Medical Institute, USA ( DT0712 to C.L.S., J.T.M., and S.L.W.), NIH /NCI/MSKCC Spore in Prostate Cancer, USA ( P50 CA092629-14 to C.L.S.), NCI /MSKCC Support Grant/Core Grant, USA ( P30CA008748-49 and P3CA008748-49-S2 to C.L.S.), the Starr Cancer Consortium, USA (I9-A9-071 to C.E.M.), the Vallee Foundation, USA (to C.E.M.), the WorldQuant Foundation, USA (to C.E.M.), the Pershing Square Sohn Cancer Research Alliance, USA (to C.E.M.), the Leukemia and Lymphoma Society, USA ( LLS 9238-16 and LLS-MCL-982 to C.E.M.), the Jackson Laboratory New Investigator Award, USA (to S.L.), the Director’s Innovation Fund, USA (to S.L.), and the NCATS ( UL1 TR001866 to Y.L.).

PY - 2020/4/13

Y1 - 2020/4/13

N2 - Metastatic prostate cancer is characterized by recurrent genomic copy number alterations that are presumed to contribute to resistance to hormone therapy. We identified CHD1 loss as a cause of antiandrogen resistance in an in vivo small hairpin RNA (shRNA) screen of 730 genes deleted in prostate cancer. ATAC-seq and RNA-seq analyses showed that CHD1 loss resulted in global changes in open and closed chromatin with associated transcriptomic changes. Integrative analysis of this data, together with CRISPR-based functional screening, identified four transcription factors (NR3C1, POU3F2, NR2F1, and TBX2) that contribute to antiandrogen resistance, with associated activation of non-luminal lineage programs. Thus, CHD1 loss results in chromatin dysregulation, thereby establishing a state of transcriptional plasticity that enables the emergence of antiandrogen resistance through heterogeneous mechanisms.

AB - Metastatic prostate cancer is characterized by recurrent genomic copy number alterations that are presumed to contribute to resistance to hormone therapy. We identified CHD1 loss as a cause of antiandrogen resistance in an in vivo small hairpin RNA (shRNA) screen of 730 genes deleted in prostate cancer. ATAC-seq and RNA-seq analyses showed that CHD1 loss resulted in global changes in open and closed chromatin with associated transcriptomic changes. Integrative analysis of this data, together with CRISPR-based functional screening, identified four transcription factors (NR3C1, POU3F2, NR2F1, and TBX2) that contribute to antiandrogen resistance, with associated activation of non-luminal lineage programs. Thus, CHD1 loss results in chromatin dysregulation, thereby establishing a state of transcriptional plasticity that enables the emergence of antiandrogen resistance through heterogeneous mechanisms.

KW - CHD1

KW - NR2F1

KW - NR3C1 (GR)

KW - POU3F2 (BRN2)

KW - TBX2

KW - antiandrogen resistantce

KW - castration-resistant prostate cancer

KW - chromatin remodeling

KW - lineage plasticity

KW - tumor heterogeneity

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U2 - 10.1016/j.ccell.2020.03.001

DO - 10.1016/j.ccell.2020.03.001

M3 - Article

C2 - 32220301

AN - SCOPUS:85082959150

VL - 37

SP - 584-598.e11

JO - Cancer Cell

JF - Cancer Cell

SN - 1535-6108

IS - 4

ER -