HDAC3 is critical in tumor development and therapeutic resistance in Kras-mutant non-small cell lung cancer [ChIP-seq KL LJE1 cells]

HDAC3 is one of the main targets of Histone Deacetylase (HDAC) inhibitors in clinical development as cancer therapies, yet the in vivo role of HDAC3 in solid tumors is unknown. Here, we identified a critical role for HDAC3 in KRAS mutant lung cancer. Using genetic engineered mouse models (GEMM), we found that HDAC3 is required for lung tumor growth in vivo. HDAC3 was found to direct and enhance the transcription effects of the lung cancer lineage transcription factor NKX2-1 to mediate expression of a common set of target genes. We identified FGFR1 as a critical new target of HDAC3. Leveraging this, we identified that an HDAC3-dependent transcriptional cassette becomes hyperactivated as KRAS/LKB1 mutant cells develop resistance to the MEK inhibitor trametinib, and this can be reversed by treatment with the HDAC1/HDAC3 inhibitor entinostat. We found that the combination of entinostat plus trametinib treatment elicits therapeutic benefit in the KRAS/LKB1 GEMM. ChIP-seq for Hdac3 and H3K27ac in KL cells.

HDAC3是组蛋白去乙酰化酶（Histone Deacetylase, HDAC）抑制剂用于癌症治疗的核心临床开发靶点之一，但HDAC3在实体瘤中的体内功能尚未明确。本研究阐明了HDAC3在KRAS突变型肺癌中的关键调控作用。借助基因工程小鼠模型（Genetically Engineered Mouse Models, GEMM），我们证实HDAC3是体内肺肿瘤生长所必需的分子。研究发现，HDAC3可直接调控并增强肺癌谱系转录因子NKX2-1的转录活性，从而介导一组共同靶基因的表达。我们还鉴定出FGFR1为HDAC3的新型关键下游靶点。基于上述发现，我们明确了当KRAS/LKB1突变细胞对MEK抑制剂曲美替尼（trametinib）产生耐药性时，HDAC3依赖的转录调控模块会发生过度激活，且该异常激活可通过HDAC1/HDAC3抑制剂恩替诺特（entinostat）治疗逆转。实验证实，恩替诺特联合曲美替尼治疗可在KRAS/LKB1基因工程小鼠模型中产生显著治疗获益。本研究针对KL细胞中的Hdac3与H3K27ac开展了染色质免疫共沉淀测序（ChIP-seq）实验。