Department of Pathology, Genentech, Inc., South San Francisco, California.
Department of Discovery Oncology, Genentech, Inc., South San Francisco, California.
Pigment Cell Melanoma Res. 2019 Mar;32(2):269-279. doi: 10.1111/pcmr.12735. Epub 2018 Sep 24.
The deubiquitinating enzyme BAP1 is mutated in a hereditary cancer syndrome with a high risk of mesothelioma and melanocytic tumors. Here, we show that Bap1 deletion in melanocytes cooperates with the constitutively active, oncogenic form of BRAF (BRAF ) and UV to cause melanoma in mice, albeit at very low frequency. In addition, Bap1-null melanoma cells derived from mouse tumors are more aggressive and colonize and grow at distant sites more than their wild-type counterparts. Molecularly, Bap1-null melanoma cell lines have increased DNA damage measured by γH2aX and hyperubiquitination of histone H2a. Therapeutically, these Bap1-null tumors are completely responsive to BRAF- and MEK-targeted therapies. Therefore, BAP1 functions as a tumor suppressor and limits tumor progression in melanoma.
去泛素化酶 BAP1 发生突变会导致一种遗传性癌症综合征，这种综合征会增加间皮瘤和黑色素瘤的患病风险。在这里，我们发现黑色素细胞中的 Bap1 缺失与持续激活的致癌型 BRAF（BRAF V600E ）以及紫外线协同作用，导致了小鼠黑色素瘤的发生，尽管其频率非常低。此外，源自于小鼠肿瘤的 Bap1 缺失型黑色素瘤细胞比野生型细胞更具侵袭性，并且能够在远处定植和生长。从分子层面来看，Bap1 缺失型黑色素瘤细胞系中 γH2aX 检测到的 DNA 损伤增加，组蛋白 H2a 的泛素化水平升高。在治疗方面，这些 Bap1 缺失型肿瘤对 BRAF 和 MEK 靶向治疗完全敏感。因此，BAP1 作为一种肿瘤抑制因子，限制了黑色素瘤的肿瘤进展。
