Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore, Singapore.
Gut. 2020 Feb;69(2):231-242. doi: 10.1136/gutjnl-2018-318025. Epub 2019 May 8.
Gastric cancer (GC) is a leading cause of cancer mortality. Previous studies have shown that is specifically overexpressed in GC and functionally required for GC development. In this study, we investigated, on a genome-wide scale, target genes of HNF4α and oncogenic pathways driven by HNF4α and HNF4α target genes.
We performed HNF4α chromatin immunoprecipitation followed by sequencing across multiple GC cell lines, integrating HNF4α occupancy data with (epi)genomic and transcriptome data of primary GCs to define HNF4α target genes of and relevance. To investigate mechanistic roles of and HNF4α targets, we performed cancer metabolic measurements, drug treatments and functional assays including murine xenograft experiments.
Gene expression analysis across 19 tumour types revealed to be specifically upregulated in GCs. Unbiased pathway analysis revealed organic acid metabolism as the top -regulated pathway, orthogonally supported by metabolomic analysis. Isocitrate dehydrogenase 1 () emerged as a convergent direct target gene regulating GC metabolism. We show that wild-type is essential for GC cell survival, and that certain GC cells can be targeted by IDH1 inhibitors.
Our results highlight a role for in sustaining GC oncogenic metabolism, through the regulation of . Drugs targeting wild-type may thus have clinical utility in GCs exhibiting overexpression, expanding the role of in cancer beyond mutated malignancies.
胃癌（GC）是癌症死亡的主要原因。先前的研究表明， 在 GC 中特异性过表达，并且对 GC 的发展具有功能上的必要性。在这项研究中，我们在全基因组范围内研究了 HNF4α 的靶基因以及由 HNF4α 和 HNF4α 靶基因驱动的致癌途径。
我们在多个 GC 细胞系中进行了 HNF4α 染色质免疫沉淀测序，将 HNF4α 占据数据与原发性 GC 的（表观）基因组和转录组数据整合，以定义 HNF4α 的靶基因和 相关性。为了研究 和 HNF4α 靶基因的机制作用，我们进行了癌症代谢测量、药物治疗和功能测定，包括小鼠异种移植实验。
在 19 种肿瘤类型中进行的基因表达分析显示， 在 GC 中特异性上调。无偏途径分析显示，有机酸代谢是上调的首要途径，代谢组学分析正交支持了这一结果。异柠檬酸脱氢酶 1（IDH1）作为直接调节 GC 代谢的 靶基因出现。我们表明，野生型 IDH1 是 GC 细胞存活所必需的，并且某些 GC 细胞可以被 IDH1 抑制剂靶向。
我们的研究结果强调了 在维持 GC 致癌代谢中的作用，通过调节 。因此，针对野生型 的药物可能在表现出 过表达的 GC 中具有临床应用价值，将 在癌症中的作用扩展到突变恶性肿瘤之外。
