Ma Sai, Zhou Bo, Yang Qian, Pan Yunzhi, Yang Wei, Freedland Stephen J, Ding Ling-Wen, Freeman Michael R, Breunig Joshua J, Bhowmick Neil A, Pan Jian, Koeffler H Phillip, Lin De-Chen
Department of Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China.
Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.
Cancer Res. 2021 Mar 1;81(5):1216-1229. doi: 10.1158/0008-5472.CAN-20-0652. Epub 2021 Jan 5.
Although obesity is one of the strongest risk factors for esophageal adenocarcinoma, the molecular mechanisms underlying this association remain unclear. We recently identified four esophageal adenocarcinoma-specific master regulator transcription factors (MRTF) ELF3, KLF5, GATA6, and EHF. In this study, gene-set enrichment analysis of both esophageal adenocarcinoma patient samples and cell line models unbiasedly underscores fatty acid synthesis as the central pathway downstream of three MRTFs (ELF3, KLF5, GATA6). Further characterizations unexpectedly identified a transcriptional feedback loop between MRTF and fatty acid synthesis, which mutually activated each other through the nuclear receptor, PPARG. MRTFs cooperatively promoted PPARG transcription by directly regulating its promoter and a distal esophageal adenocarcinoma-specific enhancer, leading to PPARG overexpression in esophageal adenocarcinoma. PPARG was also elevated in Barrett's esophagus, a recognized precursor to esophageal adenocarcinoma, implying that PPARG might play a role in the intestinal metaplasia of esophageal squamous epithelium. Upregulation of PPARG increased synthesis of fatty acids, phospholipids, and sphingolipids as revealed by mass spectrometry-based lipidomics. Moreover, ChIP-seq, 4C-seq, and a high-fat diet murine model together characterized a novel, noncanonical, and cancer-specific function of PPARG in esophageal adenocarcinoma. PPARG directly regulated the ELF3 super-enhancer, subsequently activating the transcription of other MRTFs through an interconnected regulatory circuitry. Together, elucidation of this novel transcriptional feedback loop of MRTF/PPARG/fatty acid synthesis advances our understanding of the mechanistic foundation for epigenomic dysregulation and metabolic alterations in esophageal adenocarcinoma. More importantly, this work identifies a potential avenue for prevention and early intervention of esophageal adenocarcinoma by blocking this feedback loop. SIGNIFICANCE: These findings elucidate a transcriptional feedback loop linking epigenomic dysregulation and metabolic alterations in esophageal adenocarcinoma, indicating that blocking this feedback loop could be a potential therapeutic strategy in high-risk individuals.
尽管肥胖是食管腺癌最强的风险因素之一，但这种关联背后的分子机制仍不清楚。我们最近鉴定出四种食管腺癌特异性主调控转录因子（MRTF），即ELF3、KLF5、GATA6和EHF。在本研究中，对食管腺癌患者样本和细胞系模型进行的基因集富集分析，无偏倚地强调脂肪酸合成是三种MRTF（ELF3、KLF5、GATA6）下游的核心通路。进一步的研究意外地发现了MRTF与脂肪酸合成之间的转录反馈环，它们通过核受体PPARG相互激活。MRTF通过直接调控PPARG的启动子和一个远端食管腺癌特异性增强子，协同促进PPARG转录，导致PPARG在食管腺癌中过表达。PPARG在食管腺癌的公认前驱病变巴雷特食管中也升高，这意味着PPARG可能在食管鳞状上皮的肠化生中起作用。基于质谱的脂质组学分析显示，PPARG的上调增加了脂肪酸、磷脂和鞘脂的合成。此外，染色质免疫沉淀测序（ChIP-seq）、染色体构象捕获碳拷贝测序（4C-seq）和高脂饮食小鼠模型共同揭示了PPARG在食管腺癌中一种新的、非经典的、癌症特异性功能。PPARG直接调控ELF3超级增强子，随后通过一个相互连接的调控电路激活其他MRTF的转录。总之，对MRTF/PPARG/脂肪酸合成这一新的转录反馈环的阐明，推进了我们对食管腺癌表观基因组失调和代谢改变机制基础的理解。更重要的是，这项工作确定了通过阻断这一反馈环预防和早期干预食管腺癌的潜在途径。意义：这些发现阐明了食管腺癌中连接表观基因组失调和代谢改变的转录反馈环，表明阻断这一反馈环可能是高危个体的一种潜在治疗策略。
