Department of Pathology, Anatomy, & Cell Biology, Thomas Jefferson University, Philadelphia, PA, United States.
Cancer Signaling and Epigenetics Program, Fox Chase Cancer Center, Philadelphia, PA, United States.
Cancer Lett. 2022 Oct 28;547:215885. doi: 10.1016/j.canlet.2022.215885. Epub 2022 Aug 20.
BRCA1-associated protein 1 (BAP1) is a deubiquitinase that is mutated in 10-15% of clear cell renal cell carcinomas (ccRCC). Despite the association between BAP1 loss and poor clinical outcome, the critical tumor suppressor function(s) of BAP1 in ccRCC remains unclear. Previously, we found that hypoxia-inducible factor 2α (HIF2α) and BAP1 activate interferon-stimulated gene factor 3 (ISGF3), a transcription factor activated by type I interferons and a tumor suppressor in ccRCC xenograft models. Here, we aimed to determine the mechanism(s) through which HIF and BAP1 regulate ISGF3. We found that in ccRCC cells, loss of the von Hippel-Lindau tumor suppressor (VHL) activated interferon beta (IFN-β) expression in a HIF2α-dependent manner. IFN-β was required for ISGF3 activation and suppressed the growth of Ren-02 tumors in xenografts. BAP1 enhanced the expression of IFN-β and stimulator of interferon genes (STING), both of which activate ISGF3. Both ISGF3 overexpression and STING agonist treatment increased ISGF3 activity and suppressed BAP1-deficient tumor growth in Ren-02 xenografts. Our results indicate that BAP1 loss reduces type I interferon signaling, and reactivating this pathway may be a novel therapeutic strategy for treating ccRCC.
BRCA1 相关蛋白 1（BAP1）是一种去泛素化酶，在 10-15%的透明细胞肾细胞癌（ccRCC）中发生突变。尽管 BAP1 缺失与不良临床结局之间存在关联，但 BAP1 在 ccRCC 中的关键肿瘤抑制功能仍不清楚。此前，我们发现缺氧诱导因子 2α（HIF2α）和 BAP1 可激活干扰素刺激基因因子 3（ISGF3），ISGF3 是一种由 I 型干扰素激活的转录因子，也是 ccRCC 异种移植模型中的肿瘤抑制因子。在这里，我们旨在确定 HIF 和 BAP1 调节 ISGF3 的机制。我们发现，在 ccRCC 细胞中，von Hippel-Lindau 肿瘤抑制因子（VHL）的缺失以 HIF2α 依赖的方式激活了干扰素β（IFN-β）的表达。IFN-β 是 ISGF3 激活所必需的，并且可以抑制 Ren-02 肿瘤在异种移植中的生长。BAP1 增强了 IFN-β 和干扰素基因刺激物（STING）的表达，这两者均可激活 ISGF3。ISGF3 的过表达和 STING 激动剂处理均可增加 ISGF3 活性，并抑制 Ren-02 异种移植中 BAP1 缺失肿瘤的生长。我们的研究结果表明，BAP1 的缺失会降低 I 型干扰素信号通路，而重新激活该通路可能是治疗 ccRCC 的一种新的治疗策略。
