JMJD5通过增强DNA损伤来提高顺铂在非小细胞肺癌中的化疗敏感性
JMJD5 promotes chemotherapy sensitivity of cisplatin in NSCLC by enhancing DNA damage.
摘要(中文译文)
以铂类为基础的化疗仍是晚期非小细胞肺癌（NSCLC）治疗的基石，但其疗效常因耐药而受限。JMJD5（含Jumonji结构域蛋白5）是一种具有酶活性和非酶活性的多功能蛋白，参与肿瘤进展。已有报道显示其可增强NSCLC细胞对EGFR酪氨酸激酶抑制剂（TKIs）的敏感性，但其在调控传统铂类化疗反应中的作用尚不清楚。通过患者队列的生物信息学分析评估了JMJD5的临床相关性。在A549和H1299细胞中进行的体外功能实验包括过表达建模、细胞毒性和集落形成实验、凋亡分析以及DNA损伤评估。采用酶活性失活的JMJD5突变体以解析机制。在裸鼠异种移植模型中验证了协同抗肿瘤效应。低JMJD5表达与接受化疗的NSCLC患者较差的总生存期相关，且在化疗后肿瘤组织中表达下调。顺铂处理可在体外降低JMJD5水平。恢复JMJD5表达可显著增强细胞对顺铂的敏感性，增强其抗增殖和促凋亡作用。这与DNA损伤加重相关，表现为γH2A.X升高。关键在于，该化疗增敏功能不依赖于JMJD5的酶活性。机制上，JMJD5过表达抑制了顺铂诱导的Chk1/Chk2磷酸化，提示检查点激活受损。在体内，JMJD5过表达联合顺铂显著抑制肿瘤生长，与单用顺铂相比，肿瘤体积和重量均降低。我们的结果表明，JMJD5通过非催化机制放大DNA损伤和凋亡，从而增强NSCLC对顺铂的敏感性。因此，JMJD5是克服铂类耐药的一个新的潜在靶点，为旨在恢复或稳定其表达并联合传统化疗的治疗策略提供了依据。
Abstract
Platinum-based chemotherapy remains a cornerstone in the treatment of advanced non-small cell lung cancer (NSCLC), yet its efficacy is frequently limited by drug resistance. JMJD5 (Jumonji Domain-Containing Protein 5) is a multifunctional protein implicated in tumor progression with enzymatic and non-enzymatic activities. While it has been reported to enhance the sensitivity of NSCLC cells to EGFR tyrosine kinase inhibitors (TKIs), its function in modulating response to conventional platinum chemotherapy is unknown. The clinical relevance of JMJD5 was assessed via bioinformatics analysis of patient cohorts. In vitro functional assays in A549 and H1299 cells included overexpression modeling, cytotoxicity and colony formation, apoptosis analysis, and DNA damage assessment. An enzymatically inactive JMJD5 mutant was employed to dissect mechanism. The synergistic anti-tumor effect was validated in nude mouse xenograft models. Low JMJD5 expression correlated with poorer overall survival in chemotherapy-treated NSCLC patients and was downregulated in tumor tissues post-chemotherapy. Cisplatin treatment reduced JMJD5 levels in vitro. Restoring JMJD5 expression significantly sensitized cells to cisplatin, enhancing its anti-proliferative and pro-apoptotic effects. This was associated with augmented DNA damage, evidenced by elevated γH2A.X. Crucially, the chemosensitizing function was independent of JMJD5's enzymatic activity. Mechanistically, JMJD5 overexpression suppressed cisplatin-induced Chk1/Chk2 phosphorylation, indicating impaired checkpoint activation. In vivo, JMJD5 overexpression combined with cisplatin markedly suppressed tumor growth, reducing both tumor volume and weight compared to cisplatin alone. Our results demonstrate that JMJD5 enhances cisplatin sensitivity in NSCLC by amplifying DNA damage and apoptosis through a non-catalytic mechanism. JMJD5 thus represents a novel potential target for overcoming platinum resistance, offering a rationale for therapeutic strategies aimed at restoring or stabilizing its expression in combination with conventional chemotherapy.
如何引用
AMA
Jing He, Haohao Wei, Tao Li, Qiuxiang Xiao, Guiling Liu. JMJD5 promotes chemotherapy sensitivity of cisplatin in NSCLC by enhancing DNA damage.. Biochemical and biophysical research communications. 2026; doi:10.1016/j.bbrc.2026.154270.
APA
Jing He, Haohao Wei, Tao Li, Qiuxiang Xiao, Guiling Liu (2026). JMJD5 promotes chemotherapy sensitivity of cisplatin in NSCLC by enhancing DNA damage.. Biochemical and biophysical research communications. https://doi.org/10.1016/j.bbrc.2026.154270
GB/T 7714
Jing He, Haohao Wei, Tao Li, Qiuxiang Xiao, Guiling Liu. JMJD5 promotes chemotherapy sensitivity of cisplatin in NSCLC by enhancing DNA damage.[J]. Biochemical and biophysical research communications, 2026 doi:10.1016/j.bbrc.2026.154270.
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