Histone demethylase KDM2A: Biological functions and clinical values (Review)

Liu, Lisheng; Liu, Jiangnan; Lin, Qinghai

doi:10.3892/etm.2021.10155

Cited by 30 publications

(18 citation statements)

References 80 publications

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“…In particular, NUF2 knockdown did not affect the enrichment of H3K36me and H3K36me3 in the HMGA2 promoter region in our study. This could be supported by the report that KDM2A, a Jumonji C domain-containing demethylase, specifically demethylates the H3K36me2 and exerts little or no activity on H3K36me and H3K36me3 [33]. Thus, our study contributes to further understanding the specific molecular mechanisms underlying NUF2mediated ccRCC progression.…”

Section: Discussionsupporting

confidence: 79%

NUF2 Drives Clear Cell Renal Cell Carcinoma by Activating HMGA2 Transcription through KDM2A-mediated H3K36me2 Demethylation

Lin

Chen

et al. 2022

Int. J. Biol. Sci.

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The poor sensitivity of clear cell renal cell carcinoma (ccRCC) to conventional chemotherapy and radiotherapy makes its treatment challenging. The Ndc80 kinetochore complex component (NUF2) is involved in the development and progression of several cancers. However, its role in ccRCC remains unclear. In this study, we investigated the biological functions and underlying mechanism of NUF2 in ccRCC. We found that NUF2 expression was increased in ccRCC and associated with poor prognosis. Altering NUF2 level affected cell proliferation, migration, and invasion. Moreover, NUF2 acted as a potential oncogene to promote the progression of ccRCC through epigenetic activation of high-mobility group AT-hook 2 (HMGA2) transcription by suppressing lysine demethylase 2A expression and affecting its occupancy on the HMGA2 promoter region to regulate histone H3 lysine 36 di-methylation modification. In addition, Kaplan-Meier and multivariate analysis revealed that patients whose NUF2 and HMGA2 were both elevated showed the shortest survival; and the number of upregulated markers acted as an independent predictor to evaluate survival probability. Thus, our results demonstrate that NUF2 promotes ccRCC progression, at least partly by epigenetically regulating HMGA2 transcription, and that the NUF2-HMGA2 axis could be an ideal therapeutic target and a promising prognostic indicator for ccRCC.

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Section: Discussionsupporting

confidence: 79%

NUF2 Drives Clear Cell Renal Cell Carcinoma by Activating HMGA2 Transcription through KDM2A-mediated H3K36me2 Demethylation

Lin

Chen

et al. 2022

Int. J. Biol. Sci.

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“…KDM2A plays an intriguing epigenetic regulatory role and catalyzes the demethylation of H3K36me2 [ 15 ]. Thus, we performed H3K36me2 ChIP-qPCR to characterize H3K36me2 modification at the RARRES3 promoter in KDM2A KD and control UMUC3 cells.…”

Section: Resultsmentioning

confidence: 99%

“…Lysine demethylase 2 A (KDM2A), also known as FBXL11 and JHDM1A, is highly expressed in ovarian [ 10 ], pancreatic [ 11 ], colorectal [ 12 ], breast [ 13 ], and gastric cancer [ 14 ]. As a Jumonji-C domain-containing histone demethylase, KDM2A is associated with inactively transcribed genes by demethylating the dimethylated H3K36 (H3K36me2) residue; however, it exerts little or no activity on monomethylated and trimethylated H3K36 residues [ 15 ]. H3K36me2 is enriched in both intergenic regions and gene bodies and plays an intriguing epigenetic regulatory role in cell proliferation [ 16 ], differentiation [ 17 , 18 ], and apoptosis [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

Histone H3K36me2 demethylase KDM2A promotes bladder cancer progression through epigenetically silencing RARRES3

Wei

Zhou

et al. 2022

Cell Death Dis

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Epigenetic dysregulation contributes to bladder cancer tumorigenesis. H3K36me2 demethylase KDM2A functions as an important epigenetic regulator of cell fate in many types of tumors. However, its role in bladder cancer remains unknown. Here, we revealed a positive correlation between KDM2A gene copy number gain and upregulation of KDM2A mRNA expression in bladder cancer. Moreover, a super-enhancer (SE) driving KDM2A transcription was found in high-grade bladder cancer, resulting in a significantly higher expression of KDM2A mRNA compared to that in low-grade bladder tumors. KDM2A knockdown (KD) decreased the proliferation, invasion, and spheroid formation of high-grade bladder cancer cells and inhibited tumor growth in mouse xenograft models. Furthermore, we identified RARRES3 as a key KDM2A target gene. KDM2A suppresses RARRES3 expression via demethylation of H3K36me2 in the RARRES3 promoter. Intriguingly, RARRES3 KD attenuated the inhibitory effects of KDM2A depletion on the malignant phenotypes of high-grade bladder cancer cells. The combination of the KDM2A inhibitor IOX1 and the RARRES3 agonist all-trans retinoic acid (ATRA) synergistically inhibited the proliferation of high-grade bladder cancer cells, suggesting that the KDM2A/RARRES3 axis may be a promising therapeutic target for the treatment of high-grade bladder cancer.

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“…We identify edges that are most enriched in our GWAS+ cluster which could be pointing to essential links between the gene encoding for the intermediate and containing a PrCa predisposing SNP at a particular EPIN. For example, we identify the link between MDM4 containing SNP rs35946963 (PrCa p-value 1e-24) and TP53 (Mejía-Hernández et al 2022) and between KDM2A containing SNP rs12790261 (PrCa p-value 1e-7) and BCL6 (L. Liu, Liu, and Lin 2021) and ARNT continuing SNP rs139885151 (PrCa p-value 3e-13) and HIF1A (Mandl and Depping 2017). We integrated information from pQTL associations between the 172 PrCa SNPs and protein levels (Methods).…”

Section: Network Paths With Prca Snps In the Genes Coding For Interme...mentioning

confidence: 99%

The PENGUIN approach to reconstruct protein interactions at enhancer-promoter regions and its application to prostate cancer

Armaos

Serra

Núñez-Carpintero

et al. 2022

Preprint

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DNA-binding proteins (DBPs) and in particular transcription factors interact with enhancers and their target genes through enhancer-promoter (E-P) interactions. Technological advancements such as chromosome conformation capture allow to identify E-P interactions, but the protein networks involved have not yet been characterized. Most importantly, the role of nuclear protein networks in human diseases has been so far poorly investigated. Prostate cancer (PrCa) heritability is associated with variations in enhancers that affect specific gene expression. Here, we introduce a novel approach, called Promoter-ENhancer-GUided Interaction Networks (PENGUIN), to identify protein-protein interactions (PPI) in E-P interactions and apply it to our PrCa dataset. PENGUIN integrates chromatin interactions between a promoter and its enhancers defined by high-coverage H3K27ac-HiChIP data, with a tissue-specific PPI network inferred from DNA-binding motifs and refined with gene expression. Among a total of 4,314 E-P networks, PENGUIN performed unsupervised clustering. We functionally validated this clustering procedure by searching for enrichments of specific biological features. We first validated PENGUIN structural classification of E-P networks by showing a clear differential enrichment of the architectural protein CTCF. Next, and directly related to our PrCa case study, we observed that one of our 8 main clusters, containing 273 promoters, is particularly enriched for PrCA associated single nucleotide polymorphisms (SNPs) and oncogenes. Our approach proposes a mechanistic explanation for 208 PrCa SNPs falling either inside the binding sites of DNA-binding proteins (DBPs) or within genes encoding for intermediate proteins bridging E-P contacts. PENGUIN not only confirmed the relevance of key regulators in PrCa, but also identified new candidates for intervention, opening up new directions to identify molecular targets for disease treatment.

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Histone demethylase KDM2A: Biological functions and clinical values (Review)

Cited by 30 publications

References 80 publications

NUF2 Drives Clear Cell Renal Cell Carcinoma by Activating HMGA2 Transcription through KDM2A-mediated H3K36me2 Demethylation

NUF2 Drives Clear Cell Renal Cell Carcinoma by Activating HMGA2 Transcription through KDM2A-mediated H3K36me2 Demethylation

Histone H3K36me2 demethylase KDM2A promotes bladder cancer progression through epigenetically silencing RARRES3

The PENGUIN approach to reconstruct protein interactions at enhancer-promoter regions and its application to prostate cancer

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