CANCER RESEARCH
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2024
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IF 12.5
Qiang Yulong,Fan Jiachen,Xie Chuanshuai,Yan Leilei,Song Xiaofei,Zhang Nan,Lin Yan,xiong jie,Zhang Wei,Liu Yu,Wei Lei,Li Yu,Chen Shizhen,Liang Kaiwei,Li Feng
The BET family member BRD4 is a bromodomain-containing protein that plays a vital role in driving oncogene expression. Given their pivotal role in regulating oncogenic networks in various cancer types, BET inhibitors (BETis) have been developed, but the clinical application has been impeded by dose-limiting toxicity and resistance. Understanding the mechanisms of BRD4 activity and identifying predictive biomarkers could facilitate the successful clinical use of BETis. Herein, we showed that KDM5C and BRD4 cooperate to sustain tumor cell growth. Mechanistically, KDM5C interacted with BRD4 and stimulated BRD4 enhancer recruitment. Moreover, binding of the BRD4 C-terminus to KDM5C stimulated the H3K4 demethylase activity of KDM5C. The abundance of both KDM5C-associated BRD4 and H3K4me1/3 determined the transcriptional activation of many oncogenes. Notably, depletion or pharmacological degradation of KDM5C dramatically reduced BRD4 chromatin enrichment and significantly increased BETi efficacy across multiple cancer types in both tumor cell lines and patient-derived organoid models. Furthermore, targeting KDM5C in combination with BETi suppressed tumor growth in vivo in a xenograft mouse model. Collectively, this work reveals a KDM5C-mediated mechanism by which BRD4 regulates transcription, providing a rationale for incorporating BETi into combination therapies with KDM5C inhibitors to enhance treatment efficacy.
研究领域:
肿瘤学
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分子生物学
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癌症研究
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表观遗传学
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DOI
PubMed
高影响因子
CELLULAR AND MOLECULAR LIFE SCIENCES
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2026
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IF 6.5
Zeming Lei,Liangzi Yin,Bin Zhang,Ziyuan Wang,Yansheng Wang,Lunhao Bai
Wear debris-induced periprosthetic osteolysis (PPO) is a major complication following total joint arthroplasty, leading to implant failure. Macrophage inflammatory response and osteoclastogenesis play important roles in bone destruction and resorption in PPO. KDM5C (lysine-specific demethylase 5 C), a H3K4 demethylase, functions as a transcriptional repressor in various biological processes, including immune response, energy metabolism, and neurodevelopment. However, its role in PPO pathogenesis remains unclear. In this study, we observed elevated KDM5C expression in macrophages exposed to Titanium (Ti) particles in vitro. Genetic inhibition of KDM5C attenuated Ti particle-induced upregulation of pro-inflammatory factors and reduced the release of inflammatory cytokines. Moreover, KDM5C knockdown suppressed osteoclast differentiation, as evidenced by the decrease in osteoclast number and osteoclast-specific marker expression. Mechanistically, KDM5C was found to repress NFE2L2 transcription by decreasing H3K4 trimethylation (H3K4me3) at its promoter. Inhibition of NFE2L2 abolished the protective effects of KDM5C knockdown on macrophage inflammation and osteoclast differentiation. The calvarial osteolytic model in vivo also demonstrated that silencing KDM5C alleviated Ti particle-induced bone destruction, inflammation, and osteoclastogenesis. Collectively, these findings suggest that KDM5C promotes macrophage inflammatory response and osteoclastogenesis by repressing NFE2L2 transcription through decreasing H3K4me3 levels. It may offer a novel insight into the potential therapeutic target for wear particle-induced osteolysis.
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DOI
PubMed
高影响因子
Frontiers in Molecular Neuroscience
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2026
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IF 4.4
Baoqiong Liao,Meihuan Chen,Yun Huang,Mei Shuai,Liangpu Xu,Shuwen He,Hailong Huang
Introduction Claes-Jensen syndrome is a rare X-linked syndromic neurodevelopmental disorder by pathogenic variants in lysine specific demethylase 5C ( KDM5C ), a lysine-specific histone demethylase. Methods In this study, clinical evaluations were conducted in affected individuals and carrier females. X-chromosome inactivation (XCI) assays were performed to assess genotype—phenotype correlations. Functional studies evaluated variant effects on RNA transcription, protein expression, and stability. Zebrafish models were used for in vivo validation. RNA sequencing with KEGG and GO analyses identified dysregulated genes and pathways, further confirmed in zebrafish. Results Two novel KDM5C variants NM_004187.5 :c.3019del and NM_004187.5 :c.782-2A>T were identified in unrelated families with X-linked ID. Affected males presented with short stature, microcephaly, language delay, and intellectual disability, while carrier females showed milder features including learning difficulties and short stature. Skewed XCI in some carriers suggested a role in phenotypic variability. Both variants impair RNA transcription, protein expression and stability. Zebrafish models recapitulated neurodevelopmental and behavioral abnormalities. Transcriptomic analyses revealed disrupted antiviral and interferon-related signaling, implicating aberrant immune activation. Pharmacologic inhibition of the Toll-like receptor pathway ameliorated mutant phenotypes, highlighting neuroinflammation as a potential therapeutic target for KDM5C -related disorders. Conclusion These findings expand the mutational spectrum of KDM5C -associated ID and uncover a novel pathogenic mechanism between KDM5C dysfunction, protein instability, and dysregulated inflammatory signaling.
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产品关联
DOI
PubMed
高影响因子
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