Transcriptional deregulation is a common feature of many cancers, which is often accompanied by changes in epigenetic controls. These findings have led to the development of therapeutic agents aimed at broad modulation and reprogramming of transcription in a variety of cancers. Histone Deacetylase 3, HDAC3, is one of the main targets of HDAC inhibitors currently in clinical development as cancer therapies, yet the in vivo role of HDAC3 in solid tumors is unknown. Here, we define the role of HDAC3 in two genetic engineered models of the most common subtypes of Kras-driven Non-Small Cell Lung Cancer (NSCLC), KrasG12D, STK11-/- (KL) and KrasG12D, p53-/- (KP), where we found that HDAC3 is strongly required for tumor growth of both genotypes in vivo. Transcriptional profiling and mechanistic studies revealed that HDAC3 represses p65 NF-kB-mediated induction of the Senescence Associated Secretory Program (SASP) and HDAC3 binds directly at the promoters of SASP CXC chemokines. Additionally, HDAC3 was found to cooperate with the lung cancer lineage transcription factor NKX2-1 to mediate expression of a common set of target genes. Leveraging observations about one HDAC3/NKX2-1 common target, FGFR1, we identified that an HDAC3-dependent transcriptional cassette becomes hyperactivated as Kras mutant cancer cells develop resistance to the MEK inhibitor Trametinib, and this can be rescued by treatment with the Class I HDAC inhibitor Entinostat. These unexpected findings reveal new roles for HDAC3 in proliferation control in tumors in vivo and identify specific therapeutic contexts for the utilization of HDAC3 inhibitors, whose ability to mechanistically induce SASP may be harnessed therapeutically.

中文翻译：

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HDAC3调节非小细胞肺癌的衰老和谱系特异性转录程序

转录失调是许多癌症的共同特征，通常伴随表观遗传控制的改变。这些发现导致了针对多种癌症中转录的广泛调节和重编程的治疗剂的开发。组蛋白脱乙酰基酶3（HDAC3）是目前作为癌症疗法正在临床开发中的HDAC抑制剂的主要靶标之一，但是HDAC3在实体瘤中的体内作用尚不清楚。在这里，我们定义了HDAC3在Kras驱动非小细胞肺癌（NSCLC），KrasG12D，STK11-/-（KL）和KrasG12D，p53-/-（KP）最常见亚型的两种基因工程模型中的作用），我们发现HDAC3是体内两种基因型肿瘤生长的强烈需要。转录谱分析和机理研究表明，HDAC3抑制p65 NF-kB介导的衰老相关分泌程序（SASP）的诱导，并且HDAC3直接与SASP CXC趋化因子的启动子结合。此外，发现HDAC3与肺癌谱系转录因子NKX2-1协同介导一组共同的靶基因的表达。利用关于一个HDAC3 / NKX2-1共同靶标FGFR1的观察结果，我们发现，随着Kras突变癌细胞对MEK抑制剂曲美替尼产生抗性，HDAC3依赖性转录盒变得高度活化，可以通过I类HDAC治疗来挽救抑制剂恩替司他。