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 | |
| 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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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
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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.). Publisher Copyright: © 2020 Elsevier Inc.
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
UR - http://www.scopus.com/inward/record.url?scp=85082959150&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85082959150&partnerID=8YFLogxK
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 -