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. <i>SLC7A11</i> expression is tightly controlled in normal cells and its dysregulation results in aberrant expression of <i>SLC7A11</i> in human cancers. We recently discovered that tumor suppressor BAP1, a H2A deubiquitinase, represses <i>SLC7A11</i> expression by reducing H2A ubiquitination (H2Aub) on the <i>SLC7A11</i> promoter. BAP1 inactivation in cancer cells leads to <i>SLC7A11</i> 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 <i>SLC7A11</i> expression and show that BAP1-mediated <i>SLC7A11</i> 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 <i>SLC7A11</i> promoter, both BAP1 and PRC1 represses <i>SLC7A11</i> expression, suggesting that a dynamic regulation of H2Aub is important for <i>SLC7A11</i> repression. Together, our data provide additional insights on epigenetic regulation of <i>SLC7A11</i> expression in cancer cells.