title: BAP1 inhibits the ER stress gene regulatory network and modulates metabolic stress response.
abstract: The endoplasmic reticulum (ER) is classically linked to metabolic homeostasis via the activation of unfolded protein response (UPR), which is instructed by multiple transcriptional regulatory cascades. BRCA1 associated protein 1 (BAP1) is a tumor suppressor with de-ubiquitinating enzyme activity and has been implicated in chromatin regulation of gene expression. Here we show that BAP1 inhibits cell death induced by unresolved metabolic stress. This prosurvival role of BAP1 depends on its de-ubiquitinating activity and correlates with its ability to dampen the metabolic stress-induced UPR transcriptional network. BAP1 inhibits glucose deprivation-induced reactive oxygen species and ATP depletion, two cellular events contributing to the ER stress-induced cell death. In line with this,Bap1KO mice are more sensitive to tunicamycin-induced renal damage. Mechanically, we show that BAP1 represses metabolic stress-induced UPR and cell death through activating transcription factor 3 (ATF3) and C/EBP homologous protein (CHOP), and reveal that BAP1 binds toATF3andCHOPpromoters and inhibits their transcription. Taken together, our results establish a previously unappreciated role of BAP1 in modulating the cellular adaptability to metabolic stress and uncover a pivotal function of BAP1 in the regulation of the ER stress gene-regulatory network. Our study may also provide new conceptual framework for further understanding BAP1 function in cancer.
authors.affiliation: Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030; fangyan@hematologics.com bgan@mdanderson.org.
authors.forename: Fangyan
authors.initials: F
authors.lastname: Dai
authors.affiliation: Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030.
authors.forename: Hyemin
authors.initials: H
authors.lastname: Lee
authors.affiliation: Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030.
authors.forename: Yilei
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030.
authors.forename: Li
authors.initials: L
authors.lastname: Zhuang
authors.affiliation: Department of Bioinformatics and Computations Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030.
authors.forename: Hui
authors.initials: H
authors.lastname: Yao
authors.affiliation: Division of Biostatistics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030.|Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030.
authors.forename: Yuanxin
authors.initials: Y
authors.lastname: Xi
authors.affiliation: Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030.
authors.forename: Zhen-Dong
authors.initials: ZD
authors.lastname: Xiao
authors.affiliation: Department of Hematopathology, Division of Pathology and Laboratory Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030.
authors.forename: M James
authors.initials: MJ
authors.lastname: You
authors.affiliation: Division of Biostatistics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030.|Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Bioinformatics and Computations Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Su
authors.affiliation: Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030; fangyan@hematologics.com bgan@mdanderson.org.
authors.forename: Boyi
authors.initials: B
authors.lastname: Gan
mesh_terms: D051700:Activating Transcription Factor 3 / Q000235:genetics; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D059865:Endoplasmic Reticulum Stress; D004734:Energy Metabolism; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D005947:Glucose / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D013312:Stress, Physiological; D051742:Transcription Factor CHOP / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D014415:Tunicamycin / Q000494:pharmacology; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism*; D056811:Unfolded Protein Response
chemical_list: D051700:Activating Transcription Factor 3; C575444:BAP1 protein, mouse; D017382:Reactive Oxygen Species; D025521:Tumor Suppressor Proteins; D014415:Tunicamycin; D051742:Transcription Factor CHOP; D000255:Adenosine Triphosphate; D043222:Ubiquitin Thiolesterase; D005947:Glucose
keywords: BAP1; ER stress; energy stress; glucose starvation; unfolded protein response