Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.
Simpson Querrey Center for Epigenetics, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.
Oncogene. 2022 Apr;41(15):2152-2162. doi: 10.1038/s41388-022-02240-x. Epub 2022 Feb 22.
Small cell lung cancer (SCLC) is an aggressive disease, with patients diagnosed with either early-stage, limited stage, or extensive stage of SCLC tumor progression. Discovering and targeting the functional biomarkers for SCLC will be crucial in understanding the molecular basis underlying SCLC tumorigenesis to better assist in improving clinical treatment. Emerging studies have demonstrated that dysregulations in BAP1 histone H2A deubiquitinase complex are collectively associated with pathogenesis in human SCLC. Here, we investigated the function of the oncogenic BAP1/ASXL3/BRD4 epigenetic axis in SCLC by developing a next-generation BAP1 inhibitor, iBAP-II, and focusing on the epigenetic balance established between BAP1 and non-canonical PRC1 complexes in regulating SCLC-specific transcriptional programming. We further demonstrated that pharmacologic inhibition of BAP1's catalytic activity disrupted BAP1/ASXL3/BRD4 epigenetic axis by inducing protein degradation of the ASXL3 scaffold protein, which bridges BRD4 and BAP1 at active enhancers. Furthermore, treatment of iBAP-II represses neuroendocrine lineage-specific ASCL1/MYCL/E2F signaling in SCLC cell lines, and dramatically inhibits SCLC cell viability and tumor growth in vivo. In summary, this study has provided mechanistic insight into the oncogenic function of BAP1 in SCLC and highlighted the potential of targeting BAP1's activity as a novel SCLC therapy.
小细胞肺癌（SCLC）是一种侵袭性疾病，患者被诊断为 SCLC 肿瘤进展的早期、局限期或广泛期。发现和靶向 SCLC 的功能生物标志物对于理解 SCLC 肿瘤发生的分子基础至关重要，有助于改善临床治疗。新兴研究表明，BAP1 组蛋白 H2A 去泛素化酶复合物的失调与人类 SCLC 的发病机制有关。在这里，我们通过开发下一代 BAP1 抑制剂 iBAP-II 来研究致癌 BAP1/ASXL3/BRD4 表观遗传轴在 SCLC 中的功能，并专注于 BAP1 和非典型 PRC1 复合物之间建立的表观遗传平衡，以调节 SCLC 特异性转录编程。我们进一步证明，通过诱导 ASXL3 支架蛋白的蛋白降解，BAP1 的催化活性的药理学抑制破坏了 BAP1/ASXL3/BRD4 表观遗传轴，ASXL3 支架蛋白在活性增强子处连接 BRD4 和 BAP1。此外，iBAP-II 的治疗抑制了 SCLC 细胞系中神经内分泌谱系特异性 ASCL1/MYCL/E2F 信号，并且显著抑制了体内 SCLC 细胞活力和肿瘤生长。总之，这项研究为 BAP1 在 SCLC 中的致癌功能提供了机制上的见解，并强调了靶向 BAP1 活性作为一种新型 SCLC 治疗方法的潜力。
