a Department of Experimental Radiation Oncology , the University of Texas MD Anderson Cancer Center , Houston , TX , USA.
b Department of Experimental Radiation Oncology , The University of Texas MD Anderson UTHealth Graduate School of Biomedical Sciences , Houston , TX , USA.
Cell Cycle. 2019 Apr;18(8):773-783. doi: 10.1080/15384101.2019.1597506. Epub 2019 Mar 30.
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.
SLC7A11（或 xCT）将细胞外胱氨酸导入细胞内以促进谷胱甘肽合成，从而抑制铁死亡。正常细胞中 SLC7A11 的表达受到严格控制，其失调会导致 SLC7A11 在人类癌症中的异常表达。我们最近发现，肿瘤抑制因子 BAP1（一种 H2A 去泛素化酶）通过减少 SLC7A11 启动子上的 H2A 泛素化（H2Aub）来抑制 SLC7A11 的表达。癌细胞中 BAP1 的失活导致 SLC7A11 的去抑制、铁死亡抵抗和肿瘤发生。在这里，我们表明 BAP1 促进了 I 型铁死亡诱导剂（FIN） erastin 诱导的铁死亡，但不促进 II 型 FIN RSL3 诱导的铁死亡，这进一步支持 BAP1 通过 SLC7A11 调节铁死亡。此外，我们研究了 BAP1 如何与其他转录因子协调来调节 SLC7A11 的表达，并表明 BAP1 介导的 SLC7A11 抑制不需要 NRF2 和 ATF4 转录因子。最后，我们表明，虽然 BAP1 降低了 H2Aub 结合，但 PRC1（一种主要的 H2Aub 泛素连接酶）增加了 SLC7A11 启动子上的 H2Aub 结合，BAP1 和 PRC1 都抑制了 SLC7A11 的表达，这表明 H2Aub 的动态调节对于 SLC7A11 的抑制很重要。总之，我们的数据为癌细胞中 SLC7A11 表达的表观遗传调控提供了更多的见解。
