Department of Pathology, University of Pittsburgh Medical Center, University of Pittsburgh, School of Medicine Pittsburgh, Pennsylvania; Pittsburgh Liver Research Center, University of Pittsburgh Medical Center, University of Pittsburgh, School of Medicine Pittsburgh, Pennsylvania.
Pittsburgh Liver Research Center, University of Pittsburgh Medical Center, University of Pittsburgh, School of Medicine Pittsburgh, Pennsylvania; Department of Developmental Biology, University of Pittsburgh Medical Center, University of Pittsburgh, School of Medicine Pittsburgh, Pennsylvania.
Am J Pathol. 2018 Jun;188(6):1389-1405. doi: 10.1016/j.ajpath.2018.02.006. Epub 2018 Mar 12.
Bromodomain and extraterminal (BET) proteins recruit key components of basic transcriptional machinery to promote gene expression. Aberrant expression and mutations in BET genes have been identified in many malignancies. Small molecule inhibitors of BET proteins such as JQ1 have shown efficacy in preclinical cancer models, including affecting growth of hepatocellular carcinoma. BET proteins also regulate cell proliferation in nontumor settings. We recently showed that BET proteins regulate cholangiocyte-driven liver regeneration. Here, we studied the role of BET proteins in hepatocyte-driven liver regeneration in partial hepatectomy (PHx) and acetaminophen-induced liver injury models in mice and zebrafish. JQ1 was injected 2 or 16 hours after PHx in mice to determine effect on hepatic injury, regeneration, and signaling. Mice treated with JQ1 after PHx displayed increased liver injury and a near-complete inhibition of hepatocyte proliferation. Levels of Ccnd1 mRNA and Cyclin D1 protein were reduced in animals injected with JQ1 16 hours after PHx and were even further reduced in animals injected with JQ1 2 hours after PHx. JQ1-treated zebrafish larvae after acetaminophen-induced injury also displayed notably impaired hepatocyte proliferation. In both models, Wnt signaling was prominently suppressed by JQ1. Our results show that BET proteins regulate hepatocyte proliferation-driven liver regeneration, and Wnt signaling is particularly sensitive to BET protein inhibition.
溴结构域和末端（BET）蛋白招募基本转录机制的关键组成部分，以促进基因表达。BET 基因的异常表达和突变已在许多恶性肿瘤中被发现。BET 蛋白的小分子抑制剂，如 JQ1，在临床前癌症模型中显示出疗效，包括影响肝细胞癌的生长。BET 蛋白在非肿瘤环境中也调节细胞增殖。我们最近表明，BET 蛋白调节胆管细胞驱动的肝再生。在这里，我们研究了 BET 蛋白在小鼠和斑马鱼部分肝切除（PHx）和对乙酰氨基酚诱导的肝损伤模型中对肝细胞驱动的肝再生的作用。在 PHx 后 2 或 16 小时向小鼠注射 JQ1，以确定其对肝损伤、再生和信号的影响。在 PHx 后接受 JQ1 治疗的小鼠显示出肝损伤增加，并且肝细胞增殖几乎完全受到抑制。在 PHx 后 16 小时注射 JQ1 的动物中，Ccnd1 mRNA 和 Cyclin D1 蛋白的水平降低，而在 PHx 后 2 小时注射 JQ1 的动物中，这些水平进一步降低。在乙酰氨基酚诱导损伤后的 JQ1 处理的斑马鱼幼虫中，肝细胞增殖也明显受损。在这两种模型中，JQ1 明显抑制了 Wnt 信号。我们的结果表明，BET 蛋白调节肝细胞增殖驱动的肝再生，而 Wnt 信号对 BET 蛋白抑制特别敏感。
