Uncovering BAP1 deubiquitination landscape enhances mechanism elucidation and therapeutic precision for BAP1-deficient pancancers

Jing Han Hong; Chern Han Yong; Hong Lee Heng; Xiaosai Yao; Zhimei Li; Yichen Sun; Peili Wang; Rong Xiao; Loo Chien Wang; Jianfeng Chen; Peiyong Guan; Pek Lim Chu; Takeshi Hagihara; Sheng Rong Ng; Apinya Jusakul; Sarinya Kongpetch; Amrita M. Nargund; Wern Cui Chu; Clara Shi Ya Ng; Masahiro Sugiura; Xiu Yi Kwek; Nhu An Pham; Zihao Lin; Cedric Chuan Young Ng; Abner Herbert Lim; Jing Yi Lee; Jason Yongsheng Chan; Kah Suan Lim; Wei Liu; Bin Sing Teh; Jabed Iqbal; Poramate Klanrit; Watcharin Loilome; David Wai Meng Tai; James Brugarolas; Shang Li; Radoslaw Mikolaj Sobota; Patrick Tan; Sudhakar Jha; Jing Tan; Bin Tean Teh

doi:10.1126/scitranslmed.adr6668

Uncovering BAP1 deubiquitination landscape enhances mechanism elucidation and therapeutic precision for BAP1-deficient pancancers

Jing Han Hong, Chern Han Yong, Hong Lee Heng, Xiaosai Yao, Zhimei Li, Yichen Sun, Peili Wang, Rong Xiao, Loo Chien Wang, Jianfeng Chen, Peiyong Guan, Pek Lim Chu, Takeshi Hagihara, Sheng Rong Ng, Apinya Jusakul, Sarinya Kongpetch, Amrita M. Nargund, Wern Cui Chu, Clara Shi Ya Ng, Masahiro SugiuraXiu Yi Kwek, Nhu An Pham, Zihao Lin, Cedric Chuan Young Ng, Abner Herbert Lim, Jing Yi Lee, Jason Yongsheng Chan, Kah Suan Lim, Wei Liu, Bin Sing Teh, Jabed Iqbal, Poramate Klanrit, Watcharin Loilome, David Wai Meng Tai, James Brugarolas, Shang Li, Radoslaw Mikolaj Sobota, Patrick Tan, Sudhakar Jha, Jing Tan, Bin Tean Teh

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

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Abstract

Inactivating mutations in BAP1 (BRCA1-associated protein 1) are prevalent in many aggressive cancers of high global concern, including cholangiocarcinoma, mesothelioma, uveal melanoma, and renal cell carcinoma. However, research on BAP1 has been predominantly focused on single cancer types, lacking comprehensive pancancer studies that could uncover universal molecular mechanisms and therapeutic vulnerabilities. Our pancancer study uses K-ε-GG ubiquitin remnant motif pulldown coupled with mass spectrometry to comprehensively map the landscape of proteins deubiquitinated by BAP1. Combined with transcriptomics and functional assays, we uncover previously unrecognized roles of BAP1 in enhancing global genome nucleotide excision repair (GG-NER) by modulating the deubiquitination dynamics of three GG-NER DNA damage recognition proteins, DDB1, RAD23B, and COPS7B. We also identify LSD1 (lysine-specific histone demethylase 1) and PARP1 [poly(ADP-ribose) polymerase 1] as synthetic lethal partners of BAP1 through high-throughput drug inhibitor screening. Integrative analysis using ChIP sequencing, ATAC sequencing, and transcriptomics demonstrates the colocalization of BAP1, LSD1, and PARP1 on chromatin loci, with LSD1 promoting chromatin relaxation to facilitate efficient transcription-coupled NER (TC-NER) in addition to GG-NER, whereas PARP1 facilitates lesion recognition of both TC-NER and GG-NER. Combined inhibition of LSD1 and PARP1, using SP2509/SP2577 and olaparib, respectively, synergistically hinders NER, induces apoptosis, reduces tumor burden, and prolongs the survival of multiple BAP1-deficient pancancer in vitro models and in vivo xenografts. In conclusion, our results provide a deubiquitination landscape of BAP1; elucidate the mechanisms of action of BAP1, LSD1, and PARP1 in pancancers; and describe a promising combination therapeutic strategy applicable across multiple cancers with BAP1 mutations.

Original language	English (US)
Article number	eadr6668
Pages (from-to)	eadr6668
Journal	Science translational medicine
Volume	18
Issue number	843
DOIs	https://doi.org/10.1126/scitranslmed.adr6668
State	Published - Apr 1 2026

Keywords

Cell Line, Tumor
Neoplasms/drug therapy
Precision Medicine
Poly (ADP-Ribose) Polymerase-1/metabolism
Humans
Animals
Mice
DNA Repair/drug effects
Histone Demethylases/genetics
Ubiquitination/drug effects
Phthalazines
Piperazines
Tumor Suppressor Proteins
Ubiquitin Thiolesterase

ASJC Scopus subject areas

General Medicine

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10.1126/scitranslmed.adr6668

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Hong, J. H., Yong, C. H., Heng, H. L., Yao, X., Li, Z., Sun, Y., Wang, P., Xiao, R., Wang, L. C., Chen, J., Guan, P., Chu, P. L., Hagihara, T., Ng, S. R., Jusakul, A., Kongpetch, S., Nargund, A. M., Chu, W. C., Ng, C. S. Y., ... Teh, B. T. (2026). Uncovering BAP1 deubiquitination landscape enhances mechanism elucidation and therapeutic precision for BAP1-deficient pancancers. Science translational medicine, 18(843), eadr6668. Article eadr6668. https://doi.org/10.1126/scitranslmed.adr6668

Hong, JH, Yong, CH, Heng, HL, Yao, X, Li, Z, Sun, Y, Wang, P, Xiao, R, Wang, LC, Chen, J, Guan, P, Chu, PL, Hagihara, T, Ng, SR, Jusakul, A, Kongpetch, S, Nargund, AM, Chu, WC, Ng, CSY, Sugiura, M, Kwek, XY, Pham, NA, Lin, Z, Ng, CCY, Lim, AH, Lee, JY, Chan, JY, Lim, KS, Liu, W, Teh, BS, Iqbal, J, Klanrit, P, Loilome, W, Tai, DWM, Brugarolas, J, Li, S, Sobota, RM, Tan, P, Jha, S, Tan, J & Teh, BT 2026, 'Uncovering BAP1 deubiquitination landscape enhances mechanism elucidation and therapeutic precision for BAP1-deficient pancancers', Science translational medicine, vol. 18, no. 843, eadr6668, pp. eadr6668. https://doi.org/10.1126/scitranslmed.adr6668

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title = "Uncovering BAP1 deubiquitination landscape enhances mechanism elucidation and therapeutic precision for BAP1-deficient pancancers",

abstract = "Inactivating mutations in BAP1 (BRCA1-associated protein 1) are prevalent in many aggressive cancers of high global concern, including cholangiocarcinoma, mesothelioma, uveal melanoma, and renal cell carcinoma. However, research on BAP1 has been predominantly focused on single cancer types, lacking comprehensive pancancer studies that could uncover universal molecular mechanisms and therapeutic vulnerabilities. Our pancancer study uses K-ε-GG ubiquitin remnant motif pulldown coupled with mass spectrometry to comprehensively map the landscape of proteins deubiquitinated by BAP1. Combined with transcriptomics and functional assays, we uncover previously unrecognized roles of BAP1 in enhancing global genome nucleotide excision repair (GG-NER) by modulating the deubiquitination dynamics of three GG-NER DNA damage recognition proteins, DDB1, RAD23B, and COPS7B. We also identify LSD1 (lysine-specific histone demethylase 1) and PARP1 [poly(ADP-ribose) polymerase 1] as synthetic lethal partners of BAP1 through high-throughput drug inhibitor screening. Integrative analysis using ChIP sequencing, ATAC sequencing, and transcriptomics demonstrates the colocalization of BAP1, LSD1, and PARP1 on chromatin loci, with LSD1 promoting chromatin relaxation to facilitate efficient transcription-coupled NER (TC-NER) in addition to GG-NER, whereas PARP1 facilitates lesion recognition of both TC-NER and GG-NER. Combined inhibition of LSD1 and PARP1, using SP2509/SP2577 and olaparib, respectively, synergistically hinders NER, induces apoptosis, reduces tumor burden, and prolongs the survival of multiple BAP1-deficient pancancer in vitro models and in vivo xenografts. In conclusion, our results provide a deubiquitination landscape of BAP1; elucidate the mechanisms of action of BAP1, LSD1, and PARP1 in pancancers; and describe a promising combination therapeutic strategy applicable across multiple cancers with BAP1 mutations.",

keywords = "Cell Line, Tumor, Neoplasms/drug therapy, Precision Medicine, Poly (ADP-Ribose) Polymerase-1/metabolism, Humans, Animals, Mice, DNA Repair/drug effects, Histone Demethylases/genetics, Ubiquitination/drug effects, Phthalazines, Piperazines, Tumor Suppressor Proteins, Ubiquitin Thiolesterase",

author = "Hong, \{Jing Han\} and Yong, \{Chern Han\} and Heng, \{Hong Lee\} and Xiaosai Yao and Zhimei Li and Yichen Sun and Peili Wang and Rong Xiao and Wang, \{Loo Chien\} and Jianfeng Chen and Peiyong Guan and Chu, \{Pek Lim\} and Takeshi Hagihara and Ng, \{Sheng Rong\} and Apinya Jusakul and Sarinya Kongpetch and Nargund, \{Amrita M.\} and Chu, \{Wern Cui\} and Ng, \{Clara Shi Ya\} and Masahiro Sugiura and Kwek, \{Xiu Yi\} and Pham, \{Nhu An\} and Zihao Lin and Ng, \{Cedric Chuan Young\} and Lim, \{Abner Herbert\} and Lee, \{Jing Yi\} and Chan, \{Jason Yongsheng\} and Lim, \{Kah Suan\} and Wei Liu and Teh, \{Bin Sing\} and Jabed Iqbal and Poramate Klanrit and Watcharin Loilome and Tai, \{David Wai Meng\} and James Brugarolas and Shang Li and Sobota, \{Radoslaw Mikolaj\} and Patrick Tan and Sudhakar Jha and Jing Tan and Teh, \{Bin Tean\}",

note = "Publisher Copyright: copyright {\textcopyright} 2026 The Authors, some rights reserved.",

year = "2026",

month = apr,

day = "1",

doi = "10.1126/scitranslmed.adr6668",

language = "English (US)",

volume = "18",

pages = "eadr6668",

journal = "Science translational medicine",

issn = "1946-6234",

publisher = "American Association for the Advancement of Science",

number = "843",

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TY - JOUR

T1 - Uncovering BAP1 deubiquitination landscape enhances mechanism elucidation and therapeutic precision for BAP1-deficient pancancers

AU - Hong, Jing Han

AU - Yong, Chern Han

AU - Heng, Hong Lee

AU - Yao, Xiaosai

AU - Li, Zhimei

AU - Sun, Yichen

AU - Wang, Peili

AU - Xiao, Rong

AU - Wang, Loo Chien

AU - Chen, Jianfeng

AU - Guan, Peiyong

AU - Chu, Pek Lim

AU - Hagihara, Takeshi

AU - Ng, Sheng Rong

AU - Jusakul, Apinya

AU - Kongpetch, Sarinya

AU - Nargund, Amrita M.

AU - Chu, Wern Cui

AU - Ng, Clara Shi Ya

AU - Sugiura, Masahiro

AU - Kwek, Xiu Yi

AU - Pham, Nhu An

AU - Lin, Zihao

AU - Ng, Cedric Chuan Young

AU - Lim, Abner Herbert

AU - Lee, Jing Yi

AU - Chan, Jason Yongsheng

AU - Lim, Kah Suan

AU - Liu, Wei

AU - Teh, Bin Sing

AU - Iqbal, Jabed

AU - Klanrit, Poramate

AU - Loilome, Watcharin

AU - Tai, David Wai Meng

AU - Brugarolas, James

AU - Li, Shang

AU - Sobota, Radoslaw Mikolaj

AU - Tan, Patrick

AU - Jha, Sudhakar

AU - Tan, Jing

AU - Teh, Bin Tean

PY - 2026/4/1

Y1 - 2026/4/1

N2 - Inactivating mutations in BAP1 (BRCA1-associated protein 1) are prevalent in many aggressive cancers of high global concern, including cholangiocarcinoma, mesothelioma, uveal melanoma, and renal cell carcinoma. However, research on BAP1 has been predominantly focused on single cancer types, lacking comprehensive pancancer studies that could uncover universal molecular mechanisms and therapeutic vulnerabilities. Our pancancer study uses K-ε-GG ubiquitin remnant motif pulldown coupled with mass spectrometry to comprehensively map the landscape of proteins deubiquitinated by BAP1. Combined with transcriptomics and functional assays, we uncover previously unrecognized roles of BAP1 in enhancing global genome nucleotide excision repair (GG-NER) by modulating the deubiquitination dynamics of three GG-NER DNA damage recognition proteins, DDB1, RAD23B, and COPS7B. We also identify LSD1 (lysine-specific histone demethylase 1) and PARP1 [poly(ADP-ribose) polymerase 1] as synthetic lethal partners of BAP1 through high-throughput drug inhibitor screening. Integrative analysis using ChIP sequencing, ATAC sequencing, and transcriptomics demonstrates the colocalization of BAP1, LSD1, and PARP1 on chromatin loci, with LSD1 promoting chromatin relaxation to facilitate efficient transcription-coupled NER (TC-NER) in addition to GG-NER, whereas PARP1 facilitates lesion recognition of both TC-NER and GG-NER. Combined inhibition of LSD1 and PARP1, using SP2509/SP2577 and olaparib, respectively, synergistically hinders NER, induces apoptosis, reduces tumor burden, and prolongs the survival of multiple BAP1-deficient pancancer in vitro models and in vivo xenografts. In conclusion, our results provide a deubiquitination landscape of BAP1; elucidate the mechanisms of action of BAP1, LSD1, and PARP1 in pancancers; and describe a promising combination therapeutic strategy applicable across multiple cancers with BAP1 mutations.

AB - Inactivating mutations in BAP1 (BRCA1-associated protein 1) are prevalent in many aggressive cancers of high global concern, including cholangiocarcinoma, mesothelioma, uveal melanoma, and renal cell carcinoma. However, research on BAP1 has been predominantly focused on single cancer types, lacking comprehensive pancancer studies that could uncover universal molecular mechanisms and therapeutic vulnerabilities. Our pancancer study uses K-ε-GG ubiquitin remnant motif pulldown coupled with mass spectrometry to comprehensively map the landscape of proteins deubiquitinated by BAP1. Combined with transcriptomics and functional assays, we uncover previously unrecognized roles of BAP1 in enhancing global genome nucleotide excision repair (GG-NER) by modulating the deubiquitination dynamics of three GG-NER DNA damage recognition proteins, DDB1, RAD23B, and COPS7B. We also identify LSD1 (lysine-specific histone demethylase 1) and PARP1 [poly(ADP-ribose) polymerase 1] as synthetic lethal partners of BAP1 through high-throughput drug inhibitor screening. Integrative analysis using ChIP sequencing, ATAC sequencing, and transcriptomics demonstrates the colocalization of BAP1, LSD1, and PARP1 on chromatin loci, with LSD1 promoting chromatin relaxation to facilitate efficient transcription-coupled NER (TC-NER) in addition to GG-NER, whereas PARP1 facilitates lesion recognition of both TC-NER and GG-NER. Combined inhibition of LSD1 and PARP1, using SP2509/SP2577 and olaparib, respectively, synergistically hinders NER, induces apoptosis, reduces tumor burden, and prolongs the survival of multiple BAP1-deficient pancancer in vitro models and in vivo xenografts. In conclusion, our results provide a deubiquitination landscape of BAP1; elucidate the mechanisms of action of BAP1, LSD1, and PARP1 in pancancers; and describe a promising combination therapeutic strategy applicable across multiple cancers with BAP1 mutations.

KW - Cell Line, Tumor

KW - Neoplasms/drug therapy

KW - Precision Medicine

KW - Poly (ADP-Ribose) Polymerase-1/metabolism

KW - Humans

KW - Animals

KW - Mice

KW - DNA Repair/drug effects

KW - Histone Demethylases/genetics

KW - Ubiquitination/drug effects

KW - Phthalazines

KW - Piperazines

KW - Tumor Suppressor Proteins

KW - Ubiquitin Thiolesterase

UR - https://www.scopus.com/pages/publications/105034818768

UR - https://www.scopus.com/inward/citedby.url?scp=105034818768&partnerID=8YFLogxK

U2 - 10.1126/scitranslmed.adr6668

DO - 10.1126/scitranslmed.adr6668

M3 - Article

C2 - 41920966

AN - SCOPUS:105034818768

SN - 1946-6234

VL - 18

SP - eadr6668

JO - Science translational medicine

JF - Science translational medicine

IS - 843

M1 - eadr6668

ER -

Uncovering BAP1 deubiquitination landscape enhances mechanism elucidation and therapeutic precision for BAP1-deficient pancancers

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