GATA6 induces cell senescence to exerts lung cancer suppressive function and denotes a therapeutic opportunity for GATA6 deficient lung cancer patients

Lung cancer is the world-wide leading cause of cancer related deaths. Tumor suppressor genes (TSGs) play a critical role in restricting tumorigenesis and impact the therapeutic effect of various treatments. However, TSGs remain to be systemically determined in lung cancer. Here we identified GATA6 as a potent lung cancer TSG. GATA6 inhibited lung cancer cell growth in vitro and tumorigenesis in vivo. Mechanistically, GATA6 upregulated p53 expression to transcribe p21 mRNA while inhibited Akt activation to stabilize p21 protein, thus inducing lung cancer cell senescence. Furthermore, we showed that ectopic expression of GATA6 led to dramatic shrinkage of established lung tumor in vivo A549-TetOne-GATA6 cells were treated with(positive) or without DOX (negative)for 48 h, then total RNA was isolated from cells using Trizol reagent (TAKARA, Japan). RNA libraries and RNA sequencing were performed by The Beijing Genomics Institute (BGI)

肺癌是全球范围内癌症相关死亡的首要病因。肿瘤抑制基因（tumor suppressor genes，TSGs）在抑制肿瘤发生过程中发挥关键作用，并可影响多种治疗手段的疗效。然而，肺癌中肿瘤抑制基因的系统性鉴定仍有待完成。本研究将GATA6鉴定为一种强效的肺癌肿瘤抑制基因。GATA6可在体外抑制肺癌细胞增殖，并在体内抑制肿瘤发生。机制层面，GATA6通过上调p53的表达以转录p21 mRNA，同时抑制Akt的激活以稳定p21蛋白，从而诱导肺癌细胞发生衰老。此外，本研究证实，异位表达GATA6可使体内已形成的肺部肿瘤出现显著缩小。将A549-TetOne-GATA6细胞分别用DOX（阳性组）处理48小时，或不予处理（阴性组），随后使用Trizol试剂（TAKARA，日本）从细胞中提取总RNA。RNA文库构建及RNA测序工作由北京基因组研究所（BGI）完成。