Project description:Compared to the well-established roles of apoptosis in tumor suppression, the roles and regulatory mechanisms of ferroptosis, a non-apoptotic form of cell death, in tumor biology remain much less understood. BRCA1-associated protein 1 (BAP1) encodes a nuclear de-ubiquitinating (DUB) enzyme to reduce histone 2A ubiquitination (H2Aub) on chromatin, and is a tumor suppressor in several human cancers. Here, integrated transcriptomic, epigenomic, and cancer genomic analyses link BAP1 to metabolism-related biological processes, including oxidative stress response, and identify cystine transporter SLC7A11 as a BAP1-repressed target gene with high relevance to BAP1-mediated tumor suppression in human cancers. Functional studies reveal that BAP1, in a DUB-dependent manner, decreases H2Aub occupancy on the SLC7A11 promoter and represses SLC7A11 expression, and that BAP1 inhibits cystine uptake and promotes ferroptosis through repressing SLC7A11 expression. Finally, we show that BAP1 inhibits tumor development partly through SLC7A11, and that cancer-associated BAP1 mutants lose their abilities to repress SLC7A11 and to promote ferroptosis. Together, the results of our study show that BAP1 executes its tumor suppression function at least partly through its regulation of SLC7A11 and ferroptosis, and uncover a previously unappreciated mechanism coupling ferroptosis to tumor suppression.
Project description:BRCA1-associated protein 1 (BAP1) is a tumor suppressor and its loss can result in mesothelioma, uveal and cutaneous melanoma, clear cell renal cell carcinoma and bladder cancer. BAP1 is a deubiquitinating enzyme of the UCH class that has been implicated in various cellular processes like cell growth, cell cycle progression, ferroptosis and ER metabolic stress response. Here, we identify novel BAP1 interacting proteins in the cytoplasm by expressing GFP-tagged BAP1 in an endogenous BAP1 deficient cell line using affinity purification followed by mass spec (AP-MS) analysis. Among these novel interacting proteins are all subunits of the heptameric coat protein complex I (COPI) that is involved in vesicle formation and protein cargo binding and sorting.
