Targeting TIP60 inhibits tumorigenesis in non-small cell lung cancer [ChIP-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. Comparative H4ac modification profiles of ChIP-seq data for H1975 control cells and its KD derivatives {shTIP60-1 (sh-B) and shTIP60-2 (sh-C)}.组蛋白修饰在转录激活中发挥关键作用，而异常表观遗传改变与肿瘤发生密切相关。据报道，赖氨酸（K）乙酰转移酶5（TIP60，又称KAT5）参与癌症发生发展，但其在肺癌中的功能仍不明确。本研究证实，在非小细胞肺癌细胞中敲低TIP60可抑制肿瘤细胞进展。此外，通过对肺特异性条件性敲除Tip60的小鼠肺癌模型进行分析，结果显示相较于对照组，模型组的肿瘤形成受到显著抑制，但对正常肺稳态无明显影响。通过对诱导型敲低TIP60的H1975细胞及其对照组进行RNA测序（RNA-seq）和染色质免疫共沉淀测序（ChIP-seq）分析，我们鉴定出转谷氨酰胺酶5（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体系及体内模型中抑制肿瘤生长。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或许是治疗肺癌的极具潜力的策略。针对H1975对照组细胞及其TIP60敲低衍生细胞系{shTIP60-1（sh-B）与shTIP60-2（sh-C）}的ChIP-seq数据，开展了H4乙酰化修饰（H4ac）谱的比较分析。