A Transcriptional Regulatory Loop of Master Regulator Transcription Factors, PPARG, and Fatty Acid Synthesis Promotes Esophageal Adenocarcinoma

Abstract

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 de novo 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.

Integrated Analysis of the Expression Characteristics, Prognostic Value, and Immune Characteristics of PPARG in Breast Cancer

“…The outcomes revealed that the high PPARG expression group had a higher level of immune checkpoint expression. These findings support PPARG as an additional biomarker for prognosis after immunotherapy and an additional target to facilitate corresponding immunotherapy ( Ding et al, 2020 ; Ma et al, 2021 ). However, in-depth studies are required to establish further facts.…”

Nucleolar protein NOP2 could serve as a potential prognostic predictor for clear cell renal cell carcinoma

“…As protein phosphorylation had been revealed to play vital roles in multiple cancers [37][38][39], we also analyzed the NOP2 phosphoprotein expression and found that it was highly expressed in primary ccRCC tumor than normal tissues with phosphorylation sites at the S58, T191 and S728. In order to identify NOP2-related signaling pathways, GSEA, as a useful tool, had been applied by various researchers [40,41]. Finally, five eligible signaling pathways were identified, containing cytokine-cytokine receptor interaction pathway, cytosolic DNA sensing pathway, glycerophospholipid metabolism pathway, primary immunodeficiency pathway, and intestinal immune network for IgA production pathway.…”

Widespread reorganisation of the regulatory chromatin landscape facilitates resistance to inhibition of oncogenic ERBB2 signalling

“…6P). This set of transcription factors has previously been shown to be operational in both Barrett's and OAC (Rogerson et al, 2019(Rogerson et al, , 2020Chen et al, 2020;Ma et al, 2021;Pan et al, 2020) and suggests that ERBB2 activation leads to at least partial suppression of their activity in OAC cells.…”

“…Opening regions showed 9 enrichment of motifs for a range of transcription factors which drive a gastro-intestinal programme in OAC including HNF4, GATA, FOXA, KLF and CEBP factors after 35 days (Fig. 4B; Supplementary Table 2; Rogerson et al, 2019;Chen et al, 2020;Ma et al, 2021;Pan et al, 2020). These events were already initiated after 1 day treatment (Supplementary Fig.…”

“…At the epigenetic level, the accessible chromatin landscape of BO is vastly different to the surrounding normal oesophageal tissue and this landscape is further altered during the transition to OAC (Rogerson et al, 2019;. These chromatin changes are accompanied by alterations to the transcriptional regulatory networks, with many changes to transcription factor activity being common to BO and OAC, including transcription factors like HNF4A, GATA6, FOXA, HNF1B and PPARG (Rogerson et al, 2019;Chen et al, 2020;Ma et al, 2021). Conversely, other transcription factors appear more dominant in OAC such as AP1 (Britton et al, 2017) or their regulatory activity is repurposed and directed to alternative transcriptional programmes as exemplified by KLF5 (Rogerson et al, 2020).…”