BAP1 inhibits the ER stress gene regulatory network and modulates metabolic stress response

Dai, Fengwei; Lee, Hyemin; Zhang, Yilei; Li, Zhuang; Yao, Hui; Xi, Yuanxin; Xiao, Zhilong; You, M. James; Li, Wei; Su, Xiaoping; Gan, Boyi

doi:10.1073/pnas.1619588114

Cited by 79 publications

(65 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…SLC7A11 shRNAs and SLC7A11 cDNA-containing expression vectors were described in our previous publications [18,19]. Human BAP1 cDNAs (WT and mutant) were generated as described in the our previous publication [20]. The primer sequences used in this study are listed in Table S1.…”

Section: Constructs and Reagentsmentioning

confidence: 99%

Regulation of H2A ubiquitination and SLC7A11 expression by BAP1 and PRC1

2019

Self Cite

View full text Add to dashboard Cite

SLC7A11 (or xCT) imports extracellular cystine into cells to promote glutathione synthesis, thus inhibiting ferroptosis. SLC7A11 expression is tightly controlled in normal cells and its dysregulation results in aberrant expression of SLC7A11 in human cancers. We recently discovered that tumor suppressor BAP1, a H2A deubiquitinase, represses SLC7A11 expression by reducing H2A ubiquitination (H2Aub) on the SLC7A11 promoter. BAP1 inactivation in cancer cells leads to SLC7A11 derepression, ferroptosis resistance, and tumor development. Here we show that BAP1 promotes ferroptosis induced by class I ferroptosis inducer (FIN) erastin but not by class II FIN RSL3, further supporting that BAP1 regulates ferroptosis through SLC7A11. In addition, we studied how BAP1 coordinates with other transcription factors to regulate SLC7A11 expression and show that BAP1mediated SLC7A11 repression does not require NRF2 and ATF4 transcription factors. Finally, we show that, while BAP1 decreases whereas PRC1 (a major H2Aub ubiquitin ligase) increases H2Aub binding on the SLC7A11 promoter, both BAP1 and PRC1 represses SLC7A11 expression, suggesting that a dynamic regulation of H2Aub is important for SLC7A11 repression. Together, our data provide additional insights on epigenetic regulation of SLC7A11 expression in cancer cells. ARTICLE HISTORY

show abstract

Section: Constructs and Reagentsmentioning

confidence: 99%

Regulation of H2A ubiquitination and SLC7A11 expression by BAP1 and PRC1

2019

Self Cite

View full text Add to dashboard Cite

show abstract

“…The BAP1 protein was recently demonstrated to play an important role in inhibiting apoptosis caused by metabolic stress such as glucose deprivation (48). The unfolded protein response (UPR) protects cells from stress caused by misfolded proteins in the endoplasmic reticulum (i.e., glucose deprivation), and if the stress is unresolved, this leads to induction of apoptosis by depleting ATP and generating reactive oxygen species (ROS).…”

Section: Bap1 Gene Protein Structure and Functionmentioning

confidence: 99%

“…The unfolded protein response (UPR) protects cells from stress caused by misfolded proteins in the endoplasmic reticulum (i.e., glucose deprivation), and if the stress is unresolved, this leads to induction of apoptosis by depleting ATP and generating reactive oxygen species (ROS). The investigators demonstrated that under metabolic stress, BAP1 complexes with PRC1 to promote the expression of genes essential for UPR by directly binding to the genes' promoters (48). Studies performed with several BAP1-null lung and renal cancer cell lines showed increased apoptotic induction following glucose deprivation, suggesting that the increased survival reported in patients with BAP1-negative MM may be due to the inability of these cancer cells to actively proliferate due to the stress caused by the high demand for glucose (48).…”

Section: Bap1 Gene Protein Structure and Functionmentioning

confidence: 99%

“…The investigators demonstrated that under metabolic stress, BAP1 complexes with PRC1 to promote the expression of genes essential for UPR by directly binding to the genes' promoters (48). Studies performed with several BAP1-null lung and renal cancer cell lines showed increased apoptotic induction following glucose deprivation, suggesting that the increased survival reported in patients with BAP1-negative MM may be due to the inability of these cancer cells to actively proliferate due to the stress caused by the high demand for glucose (48). Accordingly, it would be important in future work to test if BAP1-null MM tumor cells are more sensitive to ROS-promoting therapeutics.…”

Section: Bap1 Gene Protein Structure and Functionmentioning

confidence: 99%

See 1 more Smart Citation

BAP1, a tumor suppressor gene driving malignant mesothelioma

Cheung

Testa

2017

Transl. Lung Cancer Res.

View full text Add to dashboard Cite

Like cancer generally, malignant mesothelioma (MM) is a genetic disease at the cellular level. DNA copy number analysis of mesothelioma specimens has revealed a number of recurrent sites of chromosomal loss, including 3p21.1, 9p21.3, and 22q12.2. The key inactivated driver genes located at 9p21.1 and 22q12.2 were discovered two decades ago as being the tumor suppressor loci CDKN2A and NF2, respectively. Only relatively recently was the BAP1 gene determined to be the driver gene at 3p21.1 that is somatically inactivated. In 2011, we reported germline mutations in BAP1 in two families with a high incidence of mesothelioma and other cancers such as uveal melanoma (UM). As a result of a flurry of research activity over the last 5-6 years, the BAP1 gene is now firmly linked causally to a novel tumor predisposition syndrome (TPDS) characterized by increased susceptibility to mesothelioma, UM, cutaneous melanoma (CM) and benign melanocytic tumors, as well as several other cancer types. Moreover, results from recent in vivo studies with genetically engineered Bap1-mutant mouse models and new functional studies have provided intriguing biological insights regarding BAP1's role in tumorigenesis. These and other recent findings offer new possibilities for novel preventative and therapeutic strategies for MM patients.

show abstract

“…To cope with stress, the unfolded protein response (UPR) is activated, which induces a cytoprotective effect and helps to reestablish homeostasis (Yang et al, ). The UPR has three major branches: the activating transcription factor (ATF) 6 pathway, the inositol‐requiring enzyme 1α (IRE1) pathway, and the protein kinase (PKR)‐like ER kinase (PERK) pathways (Dai et al, ). To date, many studies have confirmed that ER stress involves in several physiological and pathological process, including autophagy, inflammation, metabolic diseases, and female reproduction (Cubillos‐Ruiz, Mohamed, & Rodriguez, ; Lenzen, ; Liu, Ke, & Luo, ; Yang, Pei, Jin, Wang, & Zhang, ).…”

Section: Introductionmentioning

confidence: 99%

Hormone regulates endometrial function via cooperation of endoplasmic reticulum stress and mTOR‐autophagy

Yang

Liu

Hong

et al. 2018

Journal Cellular Physiology

View full text Add to dashboard Cite

In ruminant, the receptive endometrium and the elongation of the hatched blastocyst are required to complete the process of implantation. However, the mechanisms regulating goat endometrial function during the peri-implantation period of pregnancy are still unclear. In this study, EECs were treated with progesterone, estradiol, and interferon-tau (IFNT). We have found that endoplasmic reticulum (ER) stress was activated under hormones treatment. To identify the cellular mechanism of regulation of endometrial function, we investigated the effect of ER stress activator thapsigargin (TG) and inhibitor 4 phenyl butyric acid (4-PBA) on EECs. We found that TG, which activated the three branches of UPR, increased the expression of genes associated with promoting conceptus elongation and cellular attachment, significantly up-regulated the spheroid attachment rate and PGE /PGF ratio. 4-PBA pre-treatment inhibited UPR and inhibited promoting conceptus elongation and cellular attachment related genes, but the spheroid attachment rate and PGE /PGF ratio were not changed significantly. Moreover, knockdown of ATF6 via shATF6 promoted the conceptus elongation related genes, but increased the dissolution of the corpus luteum. Besides, blocking ATF6 attenuated autophagy by activating mammalian target of rapamycin (mTOR) pathway. Moreover, rapamycin (mTOR inhibitor) pre-treatment inhibited the expression of promoting conceptus elongation and increased PGE /PGF ratio. Taken together, our study indicated that physiological level of ER stress may contribute to early pregnancy success, and ATF6 signaling pathway cooperated with autophagy to regulate endometrial function by modulating mTOR pathway.

show abstract

BAP1 inhibits the ER stress gene regulatory network and modulates metabolic stress response

Cited by 79 publications

References 36 publications

Regulation of H2A ubiquitination and SLC7A11 expression by BAP1 and PRC1

Regulation of H2A ubiquitination and SLC7A11 expression by BAP1 and PRC1

BAP1, a tumor suppressor gene driving malignant mesothelioma

Hormone regulates endometrial function via cooperation of endoplasmic reticulum stress and mTOR‐autophagy

Contact Info

Product

Resources

About