BAP1, short for BRCA1-Associated Protein 1, is a ubiquitin carboxy-terminal hydrolase functioning as a tumor suppressor. It utilizes its deubiquitinating activity to regulate multiple processes such as DNA damage repair, cell cycle control, chromatin modification, programmed cell death, and the immune response [1]. BAP1-associated pathways are crucial in maintaining normal cellular functions, and its dysregulation can lead to various cancers.

Mutations in the BAP1 gene are commonly associated with aggressive cancers like uveal melanoma, malignant mesothelioma, renal cell carcinoma, and cutaneous melanoma. Germline mutations in BAP1 have been established as a tumor predisposition syndrome, increasing the risk of hereditary, early-onset cancers [1]. Functional studies show that BAP1 decreases histone 2A ubiquitination (H2Aub) occupancy on the SLC7A11 promoter, repressing its expression and leading to elevated lipid peroxidation and ferroptosis, thereby inhibiting tumor development [2]. In CRISPR-engineered human liver organoids, BAP1 loss-of-function led to the loss of epithelial characteristics and increased motility, and restoring its catalytic activity in the nucleus rescued these changes. In a multi-mutation genetic background, BAP1 loss resulted in the acquisition of malignant features upon xenotransplantation, indicating its key role in maintaining epithelial identity through chromatin accessibility regulation [3].

In conclusion, BAP1 is a critical tumor suppressor with diverse functions in multiple cellular processes. Its inactivation, either through germline or somatic mutations, is strongly associated with the development of various cancers. Studies using models like CRISPR-engineered human liver organoids have provided valuable insights into the role of BAP1 in maintaining normal cellular states and its implications in cancer development.

References:

1. Louie, Bryan H, Kurzrock, Razelle. 2020. BAP1: Not just a BRCA1-associated protein. In Cancer treatment reviews, 90, 102091. doi:10.1016/j.ctrv.2020.102091. https://pubmed.ncbi.nlm.nih.gov/32877777/

2. Zhang, Yilei, Shi, Jiejun, Liu, Xiaoguang, Li, Wei, Gan, Boyi. 2018. BAP1 links metabolic regulation of ferroptosis to tumour suppression. In Nature cell biology, 20, 1181-1192. doi:10.1038/s41556-018-0178-0. https://pubmed.ncbi.nlm.nih.gov/30202049/

3. Artegiani, Benedetta, van Voorthuijsen, Lisa, Lindeboom, Rik G H, Vermeulen, Michiel, Clevers, Hans. 2019. Probing the Tumor Suppressor Function of BAP1 in CRISPR-Engineered Human Liver Organoids. In Cell stem cell, 24, 927-943.e6. doi:10.1016/j.stem.2019.04.017. https://pubmed.ncbi.nlm.nih.gov/31130514/