Yan QunLun, Huang Shan, Zhou Min, Deng Xin, Han Fei, Yin Hui, Xu Tao, Wang Chao, Li Yuan, Long Yang, Tang XiaoPing, Gao Yan, Dai TianYang, Hu Zhi, Han Bin, Wu Jian
Department of Thoracic Surgery, Affiliated Hospital of Southwest Medical University, Luzhou 646000, China; Department of Thoracic Surgery, Daping Hospital, Army Medical University, Chongqing 400042, China.
Department of Thoracic Surgery, Affiliated Hospital of Southwest Medical University, Luzhou 646000, China; Department of Thoracic Surgery, Suzhou Kowloon Hospital, Shanghai Jiao Tong University School of Medicine, Suzhou 215000, China.
Int J Biol Macromol. 2025 Feb;291:139152. doi: 10.1016/j.ijbiomac.2024.139152. Epub 2024 Dec 24.
Chromatin remodeling plays a pivotal role in the progression of esophageal squamous cell carcinoma (ESCC), but the precise mechanisms remain poorly understood. Here, we elucidated the critical function of staphylococcal nuclease and tudor domain-containing 1 (SND1) in modulating chromatin dynamics, thereby driving ESCC progression in both in vitro and in vivo models. Our data revealed that SND1 was markedly overexpressed in ESCC cell lines. Silencing SND1 disrupted histone modifications, attenuated RNA polymerase II activity, and precipitated increased chromosomal aberrations and DNA damage, particularly following camptothecin treatment. These molecular perturbations culminated in diminished cellular proliferation, metastasis, and chemoresistance. We further identified that the regulatory effects of SND1 on chromatin were mediated through its interaction with SMARCA5, a process potentiated by PIM1-catalyzed phosphorylation of SND1 at serine 426. This SND1-SMARCA5 interaction was essential for the transcriptional activation of CUX1, a key oncogene implicated in ESCC progression. Notably, disruption of SND1 phosphorylation impaired the SND1-SMARCA5 interaction, leading to significant inhibition of ESCC tumor growth and metastatic potential in vivo. Our findings unveil a novel mechanistic axis involving SND1 and SMARCA5 in chromatin remodeling and oncogenesis, offering promising therapeutic targets for ESCC intervention.
染色质重塑在食管鳞状细胞癌（ESCC）进展中起关键作用，但确切机制仍知之甚少。在此，我们阐明了含葡萄球菌核酸酶和 Tudor 结构域 1（SND1）在调节染色质动力学中的关键功能，从而在体外和体内模型中推动 ESCC 进展。我们的数据显示，SND1 在 ESCC 细胞系中显著过表达。沉默 SND1 会破坏组蛋白修饰，减弱 RNA 聚合酶 II 活性，并导致染色体畸变和 DNA 损伤增加，尤其是在喜树碱处理后。这些分子扰动最终导致细胞增殖、转移和化疗耐药性降低。我们进一步确定，SND1 对染色质的调节作用是通过其与 SMARCA5 的相互作用介导的，这一过程因 PIM1 在丝氨酸 426 处催化 SND1 的磷酸化而增强。这种 SND1-SMARCA5 相互作用对于 CUX1 的转录激活至关重要，CUX1 是一种与 ESCC 进展相关的关键癌基因。值得注意的是，SND1 磷酸化的破坏损害了 SND1-SMARCA5 相互作用，导致体内 ESCC 肿瘤生长和转移潜能受到显著抑制。我们的研究结果揭示了一个涉及 SND1 和 SMARCA5 的染色质重塑和肿瘤发生的新机制轴，为 ESCC 干预提供了有前景的治疗靶点。
