SNORA23-KDM5C表观遗传轴介导双重DNA修复途径，以驱动食管鳞状细胞癌的放射抗性
SNORA23-KDM5C epigenetic axis mediates dual DNA repair pathways to drive radioresistance in esophageal squamous cell carcinoma.
摘要(中文译文)
放射抵抗仍然是食管鳞状细胞癌（ESCC）的主要障碍。本研究证明小核仁RNA SNORA23是内在放射抵抗的致病性表观遗传驱动因子，其过表达与放化疗队列中的晚期T分期、淋巴结转移和不良临床结局密切相关。在机制上，SNORA23通过结构上定义的G11-Ser169界面直接结合组蛋白去甲基化酶KDM5C的ARID结构域，阻碍KDM5C的染色质结合，从而解除对DNA修复支架基因SFPQ的抑制。这种染色质重编程使SFPQ促进RAD51和Ku80募集至DNA双链断裂位点，加速同源重组（HR）和非同源末端连接（NHEJ）。SFPQ高表达可重现SNORA23介导的修复增强和放射敏感性降低。在治疗层面，靶向SNORA23的反义寡核苷酸（ASO）可破坏该轴、损害DNA修复，并与放疗协同抑制肿瘤生长、延长体内生存期，且无明显全身毒性。这些发现界定了一条驱动治疗抵抗的snoRNA-染色质-修复轴，并支持将SNORA23抑制作为克服ESCC放射抵抗的有前景策略。
Abstract
Radioresistance remains a major barrier in esophageal squamous cell carcinoma (ESCC). This study demonstrates small nucleolar RNA SNORA23 as a pathogenic epigenetic driver of intrinsic radioresistance, with its overexpression tightly correlating with advanced T-stage, lymph node metastasis, and adverse clinical outcomes in a chemoradiotherapy cohort. Mechanistically, SNORA23 directly binds the ARID domain of histone demethylase KDM5C via a structurally defined G11-Ser169 interface-obstructing KDM5C chromatin binding to derepress DNA repair scaffolding gene SFPQ. This chromatin reprogramming enables SFPQ-facilitated recruitment of RAD51 and Ku80 to DNA double-strand breaks, accelerating homologous recombination (HR) and non-homologous end joining (NHEJ). SFPQ high expression recapitulates SNORA23-mediated repair enhancement and reduced radiosensitivity. Therapeutically, SNORA23-targeting antisense oligonucleotides (ASOs) disrupt this axis, impair DNA repair, and synergize with radiotherapy to suppress tumor growth and prolong survival in vivo without evident systemic toxicity These findings define a snoRNA-chromatin-repair axis driving therapeutic resistance and support SNORA23 inhibition as a promising strategy to overcome radioresistance in ESCC.
如何引用
AMA
Baoqing Tian, Hua Zhang, Jiao Ren, Jupeng Yuan, Songyue Guo, Yue Shen, et al. SNORA23-KDM5C epigenetic axis mediates dual DNA repair pathways to drive radioresistance in esophageal squamous cell carcinoma.. Cell death and differentiation. 2026; doi:10.1038/s41418-026-01814-6.
APA
Baoqing Tian, Hua Zhang, Jiao Ren, Jupeng Yuan, Songyue Guo, Yue Shen, et al (2026). SNORA23-KDM5C epigenetic axis mediates dual DNA repair pathways to drive radioresistance in esophageal squamous cell carcinoma.. Cell death and differentiation. https://doi.org/10.1038/s41418-026-01814-6
GB/T 7714
Baoqing Tian, Hua Zhang, Jiao Ren, Jupeng Yuan, Songyue Guo, Yue Shen, et al. SNORA23-KDM5C epigenetic axis mediates dual DNA repair pathways to drive radioresistance in esophageal squamous cell carcinoma.[J]. Cell death and differentiation, 2026 doi:10.1038/s41418-026-01814-6.
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