Targeting TIP60 inhibits tumorigenesis in non-small cell lung cancer [RNA-seq]. Targeting TIP60 inhibits tumorigenesis in non-small cell lung cancer [RNA-seq]

Histone modifications play crucial roles in transcriptional activation, and aberrant epigenetic changes are associated with oncogenesis. Lysine (K) acetyltransferases 5 (TIP60, also known as KAT5) is reportedly implicated in cancer development, although its function in lung cancer remains unclear. Here we demonstrate that TIP60 knockdown in non-small cell lung cancer cells decreased tumor cell progression. Furthermore, analysis of a mouse lung cancer model with lung-specific conditional Tip60 knockout revealed suppressed tumor formation relative to controls, but no apparent effects on normal lung homeostasis. RNA-seq and ChIP-seq analyses of inducible TIP60 knockdown H1975 cells relative to controls revealed transglutaminase enzyme (TGM5) as downstream of TIP60. In addition, a candidate TIP60 inhibitor suppressed tumor growth in cell culture and in vivo. Taken together, suppression of TIP60 activity shows tumor-specific efficacy against lung cancer, with no overt effect on normal tissues. Our work suggests that targeting TIP60 could be a promising approach in treating lung cancer. Overall design: Comparative gene expression profiling analysis of RNA-seq data for H1975 control cells and its KD derivatives {shTIP60-1 (sh-B) and shTIP60-2 (sh-C)}.

组蛋白修饰（Histone modifications）在转录激活过程中发挥关键作用，异常表观遗传改变与肿瘤发生密切相关。赖氨酸（K）乙酰转移酶5（Lysine (K) acetyltransferases 5, TIP60，亦称KAT5）据报道与癌症发生存在关联，但其在肺癌中的功能仍未明确。本研究证实，在非小细胞肺癌（non-small cell lung cancer）细胞中敲低TIP60可抑制肿瘤细胞进展。此外，针对肺特异性条件性敲除Tip60的小鼠肺癌模型进行分析发现，相较于对照组，实验组肿瘤形成受到显著抑制，但对正常肺稳态无明显影响。对诱导型敲低TIP60的H1975细胞及其对照组开展转录组测序（RNA-seq）与染色质免疫共沉淀测序（ChIP-seq）分析，结果显示转谷氨酰胺酶（transglutaminase enzyme, TGM5）为TIP60的下游靶基因。此外，一种候选TIP60抑制剂可在细胞培养及体内实验中抑制肿瘤生长。综上，抑制TIP60活性对肺癌展现出肿瘤特异性疗效，且对正常组织无明显不良影响。本研究表明，靶向TIP60有望成为肺癌治疗的潜在策略。整体实验设计：对H1975对照细胞及其敲低（KD）衍生细胞系{shTIP60-1（sh-B）与shTIP60-2（sh-C）}的RNA-seq数据开展比较基因表达谱分析。