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Obesity-associated TRIM15 promotes the proliferation of esophageal adenocarcinoma through the YY2/FOXRED1 axis

ABSTRACT: Obesity has been identified as an independent risk factor for gastroesophageal reflux disease (GERD) and esophageal adenocarcinoma (EAC). Oxidative stress and inflammation driven by chronic GERD are the main causes of the tumorigenesis of EAC, but the underlying mechanism remains elusive. Here, we identified the inflammation-upregulated E3 ligase, tripartite motif 15 (TRIM15) as a key driver of obesity-associated EAC. We demonstrated that TRIM15 promotes the degradation of YY2 through the ubiquitin-proteasome system, which in turn dysregulates the lipid metabolism and enhances the proliferation of EAC cells. Furthermore, we showed that YY2 transcriptionally increases FOXRED1 expression. We then found that FOXRED1 is one of the essential effectors for the TRIM15-induced dysregulation of lipid and energy metabolism in EAC cells. Thus, we identified a novel obesity-associated TRIM15/YY2/FOXRED1 axis that contributes to the proliferation of EAC. Given that lipid metabolism regulates ferroptosis by controlling cellular processes associated with phospholipid peroxidation. We show that the TRIM15/YY2/FOXRED1 axis regulates EAC sensitivity to ferroptosis-inducing compounds by modulating the levels of SLC3A2 and GPX4, providing a therapeutic strategy for EAC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE293844 | GEO | 2026/01/28

REPOSITORIES: GEO

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			Action	DRS
		Other
	GSE293844_FOXRED1_counts.txt.gz	Txt
	GSE293844_ND_HFD_counts.txt.gz	Txt
	GSE293844_TRIM15_counts.txt.gz	Txt
	GSE293844_YY2_counts.txt.gz	Txt

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Homeostasis imbalance of YY2 and YY1 promotes tumor growth by manipulating ferroptosis

Project description:Ferroptosis is a type of programmed cell death caused by disruption of redox homeostasis, and is closely linked to amino acid metabolism. Yin Yang 2 (YY2) and its homolog Yin Yang 1 (YY1) are members of the YY family with high homology, especially in their zinc-finger domains. Furthermore, they share consensus DNA binding motif. In contrast with the oncogenic YY1, increasing evidences have demonstrated the tumor suppressive effect of YY2; however, at present, little is known about its biological and pathological functions. Here we found that YY2 induces tumor cells ferroptosis and subsequently, suppresses tumorigenesis, by inhibiting SLC7A11 transcription, leading to the decreased glutathione biosynthesis. Furthermore, we reveal that YY2 and YY1 bind competitively to SLC7A11 promoter and antagonistically regulate tumor cells ferroptosis, thus suggesting the molecular mechanism underlying their opposite regulation on tumorigenesis. Moreover, we showed that mutations of YY2 zinc-finger domains in clinical cancer patients abrogated YY2/SLC7A11 axis and tumor cells ferroptosis. Together, these results provide a new insight regarding the regulatory mechanism of ferroptosis, and a mechanistic explanation regarding the tumor suppressive effect of YY2. Furthermore, our findings demonstrate that homeostasis between YY1 and YY2 is crucial for maintaining redox homeostasis in tumor cells.

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ChIP-chip from HEK293 cells with YY2-antibody

Project description:The Yin Yang 2 (YY2) gene encodes a zinc finger transcription factor that is not well characterized, yet. By using chromatin immunoprecipitations combined with whole-genome human promoter microarray (ChIP-chip) in HEK293 cells, we identified a multiplicity of YY2-bound annotated promoters as well as additional chromosomal regions. Interestingly, gene ontology analyses linked YY2 to fundamental biological pathways associated to cancer and developmental processes. Identification of YY2 target genes in HEK293 cells in vivo

2013-06-16 | E-GEOD-22599 | biostudies-arrayexpress

Genome-wide analysis of YY2 versus YY1 target genes

Project description:Yin Yang 1 (YY1) is a critical transcription factor controlling cell proliferation, development and DNA damage responses. Although two homologous Drosophila YY family members (pleiohomeotic (pho)) and pleiohomeotic-like (phol)) are redundant, the functional significance of a recently described mammalian YY1-like gene (YY2) is unknown. Using microarray and gene set enrichment analysis (GSEA), we found that lentiviral constructs containing short hairpin loop YY1- and YY2-specific inhibitory RNAs (shYY1 and shYY2) caused significant changes in both redundant and distinguishable expression patterns. Ribosomal protein genes were the most significant gene set up-regulated by both shYY1 and shYY2, although combined shYY1/shYY2 knockdowns were not additive. In contrast, shYY2 reversed anti-proliferative effects of shYY1 on E2F target genes, and shYY2 particularly altered UV damage response, platelet-specific genes and mitochondrial function genes. The most YY2-specific gene was the platelet glycoprotein CD36 whose ligand is thrombospondin - a key UV response gene. We found that decreases in YY1 or YY2 caused inverse changes in UV sensitivity, and that their combined loss reversed their respective individual effects. Taken together, our studies show that YY2 is not redundant to YY1, and YY2 is a significant regulator of genes previously thought to uniquely respond to YY1. Functions of thrombospondin and CD36 in inflammation, atherogenesis, innate immunity and malaria pathogenesis reveal new potential regulatory roles for YY1 and YY2. Four treatment groups were used that included control vector (pLKO) virus, shYY1, shYY2 and shYY1 combined with shYY2. Three replicas were performed for all except shYY2, where we performed four replicas. Target gene comparison of YY1 And YY2 homologous genes.

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Effects of increased YY2 expression on heart development

Project description:Yin Yang 2 (YY2) is a member of the Yin Yang family of transcription factors. Although the bioactivity of YY2 has been previously studied, its role in cardiovascular diseases is not known. We observed the increased expression of YY2 in failing human hearts compared with control hearts, raising the question of whether YY2 is involved in the pathogenesis of cardiomyopathy. To investigate the potential contribution of YY2 to the development of cardiomyopathy, we crossed two transgenic (Tg) mouse lines, pCAG-YY2-Tg+ and -MHC-Cre, to generate two independent double transgenic (dTg) mouse lines in which the conditional cardiomyocyte-specific expression of YY2 driven by the -MHC promoter was mediated by Cre recombinase, starting at embryonic day 9.0. In dTg mice, we observed partial embryonic lethality and hearts with defective cardiomyocyte proliferation. Surviving dTg mice from both lines developed cardiomyopathy and heart failure that occurred with aging, showing different degrees of severity that were associated with the level of transgene expression. The development of cardiomyopathy was accompanied by increased levels of cardiac disease markers, apoptosis, and cardiac fibrosis. Our studies further revealed that the Cre-mediated cardiomyocyte-specific increase in YY2 expression led to increased levels of Beclin 1 and LC3II, indicating that YY2 is involved in mediating autophagic activity in mouse hearts in vivo. Also, compared with control hearts, dTG mouse hearts showed increased JNK activity. Because autophagy and JNK activity are important for maintaining cardiac homeostasis, the dysregulation of these signaling pathways may contribute to YY2-induced cardiomyopathy and heart failure in vivo.

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Project description:We report the application of next generation sequencing for high-throughput profiling of Yin Yang 2 (YY2) binding sites in mammalian Trophectoderm Stem cells. Sequencing of chromatin obtained in chromatin-immunoprecipitation (ChIP) assays carried out with αYY2 serum yielded over ten million sequence reads. Peak finding allowed us allowed us to identify a limited number of chromatin targets for YY2. Putative binding sites were validated in regular ChIP assays and gene expression of a few genes nearby was altered in the absence of Yy2. This study provides a framework to understand the role of YY2 in diverse mammalian cell populations.

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ChIP-chip from HEK293 cells with YY2-antibody

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Homeostasis imbalance of YY2 and YY1 promotes tumor growth by manipulating ferroptosis

Project description:Homeostasis imbalance of YY2 and YY1 promotes tumor growth by manipulating ferroptosis

| PRJNA763289 | ENA