RUVBL1/2 Complex Regulates Pro-Inflammatory Responses in Macrophages via Regulating Histone H3K4 Trimethylation

Zhang, Rui; Cheung, Chris; Seo, Sang Uk; Liu, Hang; Pardeshi, Lakhansing; Wong, Koon Ho; Chow, Larry M. C.; Chau, Mary P.; Wang, Yixiang; Lee, Ah Ra; Kwon, Woon Yong; Chen, Sheng; Chan, Bill Kwan wai; Wong, Kenneth; Choy, Richard; Ko, Ben C.B.

doi:10.3389/fimmu.2021.679184

Cited by 7 publications

(5 citation statements)

References 60 publications

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“…Consistent with our observations, the stem cell fate marker LGR5, defined as the common target of YAP and β-catenin 20 , 45 , was responsible for stem cell proliferation and H. pylori -induced gastric pathology 46 . Another common target gene for YAP and β-catenin, RUVBL1, has been reported to regulate the pro-inflammatory response of macrophages 47 . Therefore, we could speculate that RUVBL1 may be involved in H. pylori -associated gastric inflammation and lesions.…”

Section: Discussionmentioning

confidence: 99%

YAP and β-catenin cooperate to drive H. pylori -induced gastric tumorigenesis

Zhan

et al. 2023

Gut Microbes

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H. pylori infection is the strongest known risk factor for gastric carcinoma. The activation of the yes-associated protein 1 (YAP) and β-catenin pathways has been associated with multiple tumor types. In this study, we investigated the crosstalk between the YAP and β-catenin pathways in H. pylori -associated gastric tumorigenesis. Immunohistochemical analysis of YAP and β-catenin expression was performed in human gastric cancer tissues. The small molecules Super-TDU and KYA1797K, pharmacological inhibitors of YAP and β-catenin, respectively, were used to investigate the role of these signaling pathways in H. pylori -induced gastric carcinogenesis in murine models of infection. The common downstream targets of YAP and β-catenin signaling were evaluated by RNA sequencing (RNA-seq). Western blot, immunofluorescence, luciferase, RT-PCR, immunoprecipitation, cell counting kit-8 (CCK8), EdU and spheroid assays were used. H. pylori infection promoted YAP and β-catenin nuclear accumulation and transcriptional activity in gastric epithelial cells and transgenic insulin–gastrin (INS-GAS) mice, whereas silencing of both YAP and β-catenin synergistically inhibited H. pylori- induced cell proliferation and expansion. In addition, YAP was found to directly interact with β-catenin and knockdown of YAP suppressed H. pylori -induced nuclear translocation of β-catenin. Moreover, downstream genes caudal-type homeobox 2 (CDX2), leucine-rich repeat containing G protein-coupled receptor 5 (LGR5) and RuvB like AAA ATPase 1 (RUVBL1) were shared by both YAP and β-catenin signaling. Furthermore, treatment with the YAP inhibitor Super-TDU or β-catenin inhibitor KYA1797A significantly alleviated gastric inflammation and epithelial DNA damage in H. pylori -infected mice. Finally, the elevation of gastric YAP was positively correlated with β-catenin expression in human gastric cancer tissues. These findings indicate that YAP and β-catenin synergistically promote H. pylori -induced gastric carcinogenesis via their physical interaction and reveal that CDX2, LGR5 and RUVBL1 are the downstream genes shared by both the YAP and β-catenin signaling pathways, and potentially contribute to H. pylori pathogenesis.

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Section: Discussionmentioning

confidence: 99%

YAP and β-catenin cooperate to drive H. pylori -induced gastric tumorigenesis

Zhan

et al. 2023

Gut Microbes

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“…During hypoxia, Reptin52 ATP-binding protein translocates from nucleus to cytoplasm and colocalizes with HIF-2α upon ERK1/2 inhibition in HeLa cells, suggesting that Reptin52 may reduce HIF-2α nuclear activity by a non-canonical PHD-VHL-proteasome independent mechanism [ 74 ]. This may be an attempt to dampen macrophage inflammation as transcriptome analysis in macrophages suggests that Reptin52 (RUVBL2) is an integral component of macrophage pro-inflammatory responses including NO production [ 141 ]. Myeloid HIF-2α suppresses NO production by competitive usage of L-arginine away from HIF-1α-driven iNOS-generated NO [ 62 ].…”

Section: Discussionmentioning

confidence: 99%

The Underexplored Landscape of Hypoxia-Inducible Factor 2 Alpha and Potential Roles in Tumor Macrophages: A Review

Steinberger

Eubank

2023

Oxygen

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Low tissue oxygenation, termed hypoxia, is a characteristic of solid tumors with negative consequences. Tumor-associated macrophages (TAMs) accumulate in hypoxic tumor regions and correlate with worse outcomes in cancer patients across several tumor types. Thus, the molecular mechanism in which macrophages respond to low oxygen tension has been increasingly investigated in the last decade. Hypoxia stabilizes a group of hypoxia-inducible transcription factors (HIFs) reported to drive transcriptional programs involved in cell survival, metabolism, and angiogenesis. Though both tumor macrophage HIF-1α and HIF-2α correlate with unfavorable tumor microenvironments, most research focuses on HIF-1α as the master regulator of hypoxia signaling, because HIF-1α expression was originally identified in several cancer types and correlates with worse outcome in cancer patients. The relative contribution of each HIFα subunit to cell phenotypes is poorly understood especially in TAMs. Once thought to have overlapping roles, recent investigation of macrophage HIF-2α has demonstrated a diverse function from HIF-1α. Little work has been published on the differential role of hypoxia-dependent macrophage HIF-2α when compared to HIF-1α in the context of tumor biology. This review highlights cellular HIF-2α functions and emphasizes the gap in research investigating oxygen-dependent functions of tumor macrophage HIF-2α.

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“…In a study of the tumor microenvironment, JMJD3 advanced the tumor-associated macrophage polarization to the M1 phenotype 18 ; In addition to H3K27me3, H3K4me3 is involved in macrophagemediated inflammation. 30 Based on the common regulatory characteristics of H3K27me3 and H3K4me3 demethylation in mouse macrophage inflammation [30][31][32] considering the role of JMJD3 is crucial.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to H3K27me3, H3K4me3 is involved in macrophage‐mediated inflammation 30 . Based on the common regulatory characteristics of H3K27me3 and H3K4me3 demethylation in mouse macrophage inflammation 30–32 considering the role of JMJD3 is crucial. Therefore, we assessed the mechanism of JMJD3‐mediated regulation of M1/M2 phenotype conversion in LPS‐induced ALI, focussing on JMJD3‐mediated demethylation of H3K27me3 and H3K4me3 17 .…”

Section: Discussionmentioning

confidence: 99%

JMJD3 downregulates IL4i1 aggravating lipopolysaccharide‐induced acute lung injury via H3K27 and H3K4 demethylation

Gao

Wang

Jia

2022

Environmental Toxicology

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The pro‐inflammation M1 to anti‐inflammation M2 macrophage ratio contribute to the severity of lipopolysaccharide (LPS)‐induced acute lung injury (ALI). JMJD3 aggravates the inflammatory reaction through affecting epigenetic modification and macrophage's phenotype to deteriorate ALI. To explore the mechanism underlying the upregulation of the macrophage M1/M2 ratio through JMJD3, we developed an ALI mouse model using intratracheal LPS, LPS‐stimulated RAW 264.7 cells, and inhibited JMJD3 using GSK‐J4. H3K27me3 and H3K4me3 were investigated as JMJD3‐mediated epigenetic alteration sites in vivo and in vitro. C/EBPβ and KDM5A were validated as linking factors between H3K27 and H3K4. IL4i1 was investigated as a JMJD3‐mediated targeted gene to regulate the macrophage M1/M2 ratio. Chromatin immunoprecipitation was used to evaluate the relationship between H3K27me3 and C/ebpβ, C/EBPβ and Kdm5a, H3K4me3 and Il4i1. Inhibiting JMJD3 with GSK‐J4 can relieve inflammation and pathological performance in ALI. JMJD3 can reduce IL4i1 expression to increase the macrophage M1/M2 ratio and aggravated ALI which process was mediated via JMJD3‐indcued H3K27me3 and H3K4me3 demethylation, latter H3K4me3 demethylation inhibited IL4i1 transcription. Inhibiting JMJD3 with GSK‐J4 can increase IL4i1 expression, subsequently decreasing the expressions of M1 and increasing of M2 in vivo. The over‐expression IL4i1 in LPS‐stimulated macrophage or inhibiting JMJD3 with GSK‐J4 can both reverse the increase of the macrophage M1/M2 ratio in vitro. C/EBPβ and KDM5A were upregulated by LPS simulation, which linked JMJD3‐induced H3K27‐H3K4 demethylation. JMJD3 inhibited IL4i1 to increase the macrophage M1/M2 phenotype ratio and aggravate LPS‐induced ALI. Using GSK‐J4 to inhibit JMJD3 may facilitate the treatment of LPS‐induced ALI.

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RUVBL1/2 Complex Regulates Pro-Inflammatory Responses in Macrophages via Regulating Histone H3K4 Trimethylation

Cited by 7 publications

References 60 publications

YAP and β-catenin cooperate to drive H. pylori -induced gastric tumorigenesis

YAP and β-catenin cooperate to drive H. pylori -induced gastric tumorigenesis

The Underexplored Landscape of Hypoxia-Inducible Factor 2 Alpha and Potential Roles in Tumor Macrophages: A Review

JMJD3 downregulates IL4i1 aggravating lipopolysaccharide‐induced acute lung injury via H3K27 and H3K4 demethylation

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