LHX9 rescues KRAS suppression through transcriptional regulation of YAP1 [RNA-Seq]. LHX9 rescues KRAS suppression through transcriptional regulation of YAP1 [RNA-Seq]

Oncogenic KRAS signaling is required for tumor survival in cancers that harbor KRAS mutations. We recently performed a genome-scale expression screen to identify genes that bypass KRAS dependency. Here we demonstrate that the developmental transcription factor LHX9 rescues KRAS suppression in vitro and xenograft models. Furthermore, LHX9 decreases cell sensitivity to KRASG12C and MEK1/2 inhibitors. LHX9 promotes transcriptional changes associated with KRAS. Importantly, YAP1 upregulation by LHX9 is required for the rescue of KRAS suppression. Together we identify LHX9 as a YAP1 transcriptional regulator that permits KRAS-dependent cells to proliferate without KRAS expression. Overall design: mRNA profiles of HCT116 cells expressing different open reading frames and tet-inducible shKRAS were generated by sequencing, in duplicates, using Illumina Hiseq-2500

在携带KRAS突变的癌症中，致癌性KRAS信号通路是肿瘤存活所必需的。本课题组近期开展全基因组表达筛选，旨在鉴定可绕过KRAS依赖的基因。本研究证实，发育转录因子LHX9可在体外及异种移植模型中挽救KRAS抑制效应。此外，LHX9可降低细胞对KRASG12C与MEK1/2抑制剂的敏感性。LHX9可促进与KRAS相关的转录组改变。尤为重要的是，LHX9介导的YAP1上调是挽救KRAS抑制效应的必要条件。综上，本研究鉴定出LHX9是一种YAP1转录调控因子，可使依赖KRAS的细胞在不表达KRAS的情况下仍能增殖。整体实验设计：采用Illumina Hiseq-2500测序平台，对表达不同开放阅读框（open reading frames, ORF）及四环素诱导型shKRAS的HCT116细胞进行双重复测序，以获取其mRNA表达谱。