Role of the Epigenetic Modifier JMJD6 in Tumor Development and Regulation of Immune Response

Wang, Kai; Yang, Chao; Li, Haibin; Liu, Xiaoyan; Zheng, Meiling; Xuan, Zixue; Mei, Zhiqiang

doi:10.3389/fimmu.2022.859893

Cited by 11 publications

(8 citation statements)

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“…These results suggest that SOX9 expression may be able to regulate TME homeostasis by modulating various immune cells and immunomodulatory genes. The immune checkpoint pathway is a mechanism used by tumor cells to disguise themselves as normal components of the human body (44)(45)(46). In addition, SOX9 was mutually exclusive with a variety of tumor immune checkpoints (CD27, CTLA4, LAG3, TIGIT, IL10, CSF1R, ADORA2A, CD244, etc.…”

Section: Discussionmentioning

confidence: 99%

“…The expression data of the SOX9 gene and 150 marker genes of five immune pathways (chemokines (41), receptors (18), MHCs (21), immunoinhibitors (24) and immunostimulators (46)) in each tumor sample were extracted from the downloaded pan-cancer dataset (TCGA Pan-Cancer (PANCAN, N = 10,535; G = 60,499)), filtered all normal samples, and a log2(x + 0.001) transformation was performed for each expression value. Finally, a Pearson correlation was calculated between SOX9 and the five types of marker genes.…”

Section: Immunomodulatory Genetic Analysismentioning

confidence: 99%

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Comprehensive analysis, immune, and cordycepin regulation for SOX9 expression in pan-cancers and the matched healthy tissues

Yang

et al. 2023

Front. Immunol.

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SRY-box transcription factor 9 (SOX9) (OMIM 608160) is a transcription factor. The expression of SOX9 in pan-cancers and the regulation by small molecules in cancer cell lines are unclear. In the current study, we comprehensively analyzed the expression of SOX9 in normal tissues, tumor tissues and their matched healthy tissues in pan-cancers. The study examined the correlation between immunomodulators and immune cell infiltrations in normal and tumor tissues. Cordycepin (CD), an adenosine analog for SOX9 expression regulation, was also conducted on cancer cells. The results found that SOX9 protein is expressed in a variety of organs, including high expression in 13 organs and no expression in only two organs; in 44 tissues, there was high expression in 31 tissues, medium expression in four tissues, low expression in two tissues, and no expression in the other seven tissues. In pan-cancers with 33 cancer types, SOX9 expression was significantly increased in fifteen cancers, including CESC, COAD, ESCA, GBM, KIRP, LGG, LIHC, LUSC, OV, PAAD, READ, STAD, THYM, UCES, and UCS, but significantly decreased in only two cancers (SKCM and TGCT) compared with the matched healthy tissues. It suggests that SOX9 expression is upregulated in the most cancer types (15/33) as a proto-oncogene. The fact that the decrease of SOX9 expression in SKCM and the increase of SOX9 in the cell lines of melanoma inhibit tumorigenicity in both mouse and human ex vivo models demonstrates that SOX9 could also be a tumor suppressor. Further analyzing the prognostic values for SOX9 expression in cancer individuals revealed that OS is long in ACC and short in LGG, CESC, and THYM, suggesting that high SOX9 expression is positively correlated with the worst OS in LGG, CESC, and THYM, which could be used as a prognostic maker. In addition, CD inhibited both protein and mRNA expressions of SOX9 in a dose-dependent manner in 22RV1, PC3, and H1975 cells, indicating CD’s anticancer roles likely via SOX9 inhibition. Moreover, SOX9 might play an important role in tumor genesis and development by participating in immune infiltration. Altogether, SOX9 could be a biomarker for diagnostics and prognostics for pan-cancers and an emerging target for the development of anticancer drugs.

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Section: Discussionmentioning

confidence: 99%

Section: Immunomodulatory Genetic Analysismentioning

confidence: 99%

Comprehensive analysis, immune, and cordycepin regulation for SOX9 expression in pan-cancers and the matched healthy tissues

Yang

et al. 2023

Front. Immunol.

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“…Jmjd6 is an arginine demethylase which preferentially demethylates asymmetric demethylation thus potentially lowering ADMA generation [57][58][59]. However, the impact of jmjd6 expression on tumor progression is contradictory and dependent on the tumor type [60][61][62]. The relative expression level of PRMT and jmjd6 therefore may provide additional insights for the regulation of ADMA production in tumor cells, depending on specific tumor type.…”

Section: Discussionmentioning

confidence: 99%

Tumor cell-derived asymmetric dimethylarginine regulates macrophage functions and polarization

et al. 2022

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Background Asymmetric dimethylarginine (ADMA), which is significantly elevated in the plasma of cancer patients, is formed via intracellular recycling of methylated proteins and serves as a precursor for resynthesis of arginine. However, the cause of ADMA elevation in cancers and its impact on the regulation of tumor immunity is not known. Methods Three mouse breast cell lines (normal breast epithelial HC11, breast cancer EMT6 and triple negative breast cancer 4T1) and their equivalent 3D stem cell culture were used to analyze the secretion of ADMA using ELISA and their responses to ADMA. Bone marrow-derived macrophages and/or RAW264.7 cells were used to determine the impact of increased extracellular ADMA on macrophage-tumor interactions. Gene/protein expression was analyzed through RNAseq, qPCR and flow cytometry. Protein functional analyses were conducted via fluorescent imaging (arginine uptake, tumor phagocytosis) and enzymatic assay (arginase activity). Cell viability was measured via MTS assay and/or direct cell counting using Countess III FL system. Results For macrophages, ADMA impaired proliferation and phagocytosis of tumor cells, and even caused death in cultures incubated without arginine. ADMA also led to an unusual macrophage phenotype, with increased expression of arginase, cd163 and cd206 but decreased expression of il10 and dectin-1. In contrast to the severely negative impacts on macrophages, ADMA had relatively minor effects on proliferation and survival of mouse normal epithelial HC11 cells, mouse breast cancer EMT6 and 4T1 cells, but there was increased expression of the mesenchymal markers, vimentin and snail2, and decreased expression of the epithelial marker, mucin-1 in EMT6 cells. When tumor cells were co-cultured ex vivo with tumor antigen in vivo-primed splenocytes, the tumor cells secreted more ADMA and there were alterations in the tumor cell arginine metabolic landscape, including increased expression of genes involved in arginine uptake, metabolism and methylation, and decreased expression of a gene that is responsible for arginine demethylation. Additionally, interferon-gamma, a cytokine involved in immune challenge, increased secretion of ADMA in tumor cells, a process attenuated by an autophagy inhibitor. Conclusion Our results suggest initial immune attack promotes autophagy in tumor cells, which then secrete ADMA to manipulate macrophage polarization favoring tumor tolerance.

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“…236 JMJD6, another JmjC-containing iron and 2-oxoglutarate-dependent dioxygenase, can demethylate histone H3 arginine 2 (H3R2me2) and histone H4 arginine 3 (H4R3me2) as an arginine demethylase by removing methyl groups. 233,237,238 Furthermore, JMJD1B can regulate the demethylation of H3K9me2, and then regulate the demethylation of H4R3me2/me1, which is closely related to the growth of hematopoietic stem cells (Fig. 5).…”

Section: Histone Demethylases (Hdmts)mentioning

confidence: 99%

Targeting epigenetic regulators to overcome drug resistance in cancers

Wang

2023

Sig Transduct Target Ther

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Drug resistance is mainly responsible for cancer recurrence and poor prognosis. Epigenetic regulation is a heritable change in gene expressions independent of nucleotide sequence changes. As the common epigenetic regulation mechanisms, DNA methylation, histone modification, and non-coding RNA regulation have been well studied. Increasing evidence has shown that aberrant epigenetic regulations contribute to tumor resistance. Therefore, targeting epigenetic regulators represents an effective strategy to reverse drug resistance. In this review, we mainly summarize the roles of epigenetic regulation in tumor resistance. In addition, as the essential factors for epigenetic modifications, histone demethylases mediate the histone or genomic DNA modifications. Herein, we comprehensively describe the functions of the histone demethylase family including the lysine-specific demethylase family, the Jumonji C-domain-containing demethylase family, and the histone arginine demethylase family, and fully discuss their regulatory mechanisms related to cancer drug resistance. In addition, therapeutic strategies, including small-molecule inhibitors and small interfering RNA targeting histone demethylases to overcome drug resistance, are also described.

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Role of the Epigenetic Modifier JMJD6 in Tumor Development and Regulation of Immune Response

Cited by 11 publications

References 89 publications

Comprehensive analysis, immune, and cordycepin regulation for SOX9 expression in pan-cancers and the matched healthy tissues

Comprehensive analysis, immune, and cordycepin regulation for SOX9 expression in pan-cancers and the matched healthy tissues

Tumor cell-derived asymmetric dimethylarginine regulates macrophage functions and polarization

Targeting epigenetic regulators to overcome drug resistance in cancers

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