KDM6B (Lysine Demethylase 6B)

Functional assays further demonstrate that YTHDF3 knockdown enhances cisplatin sensitivity in bladder cancer cells and xenograft tumors, whereas enforced expression of KDM6B or CDKN1A phenocopies the cisplatin-sensitizing effect of YTHDF3 knockdown. Collectively, our findings define a lactate-AARS2-YTHDF3-KDM6B-CDKN1A axis that integrates metabolic reprogramming, m6A-dependent epitranscriptomic regulation, and epigenetic chromatin remodeling to drive cisplatin resistance in bladder cancer.

Temporally controlled Sox10 induction partially rescued myelination in Kdm6b -cKO mice. These findings define a KDM6B→SOX10 axis that licenses oligodendrocyte development and cortical myelination by removing repressive H3K27me3 and sustaining active chromatin, with implications for KDM6B-related neurodevelopmental disorders.

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Concurrently, GSK-J4 played a role in preventing TGFβ1-triggered EMT, invasion, and migration. Consequently, targeting histone methylation modification and the small molecule inhibitor GSK-J4 is anticipated to be an effective treatment strategy and a novel method for NSCLC.

This study provides a promising scaffold for developing selective KDM6B inhibitors, as well as delivers a tool compound for probing the biological functions of KDM6B. These findings offer a potential lead for future KDM6B-targeted drug discovery.

More importantly, KDM6B knockdown conferred resistance to anti-PD-1 therapy in CRC, whereas its overexpression synergized with anti-PD-1 therapy. In conclusion, this study establishes the KDM6B-SLC10A2 axis as a novel epigenetic immune checkpoint, highlighting its potential as a therapeutic target for reprogramming the immunosuppressive microenvironment in CRC.

Together, the findings reveal a lineage-selective transcription, with histone epigenomics-dependent role for nap1l4a in vertebrate primitive erythropoiesis. These findings highlight potential mechanisms underlying human blood disorders and hypoxia responses associated with Nap1l4a deficiency.

Finally, in vivo experiments using patient-derived xenograft (PDX) models demonstrated that Gskj1 effectively enhances the antitumor efficacy of chemotherapy in SCLC, providing compelling evidence for the clinical potential of targeting KDM6B to overcome chemoresistance.

Collectively, our study provides new insights into the epigenetic etiology of OSCC that reveals the interplay between serine metabolism and epigenetic molecular mechanisms driving OSCC cell plasticity and tumorigenesis. The dependence of OSCC cells on exogenous serine to maintain plastic cell states offers a unique opportunity to utilize a non-toxic dietary serine restriction as an intervention treatment either alone or in combination with other therapies for OSCC patients.

KDM6A and KDM6B also contribute to the regulation of therapeutic insensitivity to chemotherapy, targeted response, radiotherapy and immunotherapy. Herein, we outline the current knowledge of KDM6A/B in regulation of therapeutic resistance, and suggest that KDM6A/B holds immense potential in recovering therapeutic resistance.

The 4 MRGs may contribute to the understanding on UPRmt in LUAD and the development of relevant medicine in clinical practice.

GSK-J4 increased histone3 lysine27 trimethylation (H3K27me3) enrichment at MMP-11 and -16 promoters, as shown by Chromatin Immunoprecipitation (ChIP). KDM6A demethylates H3K27me3 at MMP-11 and -16 promoters, sustaining their enhanced expression in PCa and revealing a novel epigenetic mechanism driving metastasis-associated protease expression.