Regulation of H2A ubiquitination and SLC7A11 expression by BAP1 and PRC1

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 suppre...

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Vydané v:	Cell cycle (Georgetown, Tex.) Ročník 18; číslo 8; s. 773 - 783
Hlavní autori:	Zhang, Yilei, Koppula, Pranavi, Gan, Boyi
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	United States Taylor & Francis 18.04.2019
Predmet:	Activating Transcription Factor 4 - metabolism Amino Acid Transport System y+ - genetics Amino Acid Transport System y+ - metabolism BAP1 Cell Cycle Proteins - metabolism Cell Line, Tumor Cell Survival - drug effects Extra View ferroptosis Ferroptosis - drug effects Ferroptosis - genetics Gene Expression Regulation, Neoplastic Gene Knockdown Techniques H2A ubiquitination HEK293 Cells Histones - metabolism Humans Neoplasms - metabolism NF-E2-Related Factor 2 - metabolism Piperazines - pharmacology PRC1 Promoter Regions, Genetic SLC7A11 Transfection Tumor Suppressor Proteins - genetics Tumor Suppressor Proteins - metabolism Ubiquitin Thiolesterase - genetics Ubiquitin Thiolesterase - metabolism Ubiquitination H2A ubiquitination ferroptosis SLC7A11 PRC1 BAP1
ISSN:	1538-4101, 1551-4005, 1551-4005
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Shrnutí:	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 de-repression, 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 BAP1-mediated 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.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1538-4101 1551-4005 1551-4005
DOI:	10.1080/15384101.2019.1597506