As our comprehension of the intricate relationship between cellular senescence and tumor biology continues to evolve, the therapeutic potential of cellular senescence is gaining increasing recognition. Here, we identify chromobox 4 (CBX4), a Small Ubiquitin-related Modifier (SUMO) E3 ligase, as an antagonist of cellular senescence and elucidate a novel mechanism by which CBX4 promotes drug resistance and malignant progression of gastric cancer (GC). and models were conducted to investigate the manifestation and impact of CBX4 on cellular senescence and chemoresistance. High-throughput sequencing, chromatin immunoprecipitation, and co-immunoprecipitation techniques were utilized to identify the upstream regulators and downstream effectors associated with CBX4, revealing its intricate regulatory network. CBX4 diminishes the sensitivity of GC cells to cellular senescence, facilitating chemoresistance and GC development by deactivating the senescence-related Hippo pathway. Mechanistically, low-dose cisplatin transcriptionally downregulates CBX4 through CEBPB. In addition, CBX4 preserves the stability and cytoplasm-nuclear transport of YAP1, the key player of Hippo pathway, by inducing SUMO1 modification at K97 and K280, which competitively inhibits YAP1-S127 phosphorylation. Our study highlights the anti-senescence role of CBX4 and suggests that CBX4 inhibition in combination with low-dose cisplatin has the potential to overcome chemoresistance and effectively restrict GC progression.

中文翻译：

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CBX4 通过诱导 YAP1 SUMO 化来对抗细胞衰老，使胃癌细胞对化疗脱敏


随着我们对细胞衰老与肿瘤生物学之间错综复杂关系的理解不断发展，细胞衰老的治疗潜力越来越得到人们的认可。在这里，我们鉴定了 chromobox 4 (CBX4)，一种小泛素相关修饰符 (SUMO) E3 连接酶，作为细胞衰老的拮抗剂，并阐明了 CBX4 促进胃癌 (GC) 耐药性和恶性进展的新机制。并建立模型来研究 CBX4 对细胞衰老和化疗耐药的表现和影响。利用高通量测序、染色质免疫沉淀和免疫共沉淀技术来鉴定与 CBX4 相关的上游调控因子和下游效应因子，揭示其复杂的调控网络。 CBX4 降低 GC 细胞对细胞衰老的敏感性，通过停用衰老相关的 Hippo 途径促进化疗耐药和 GC 发展。从机制上讲，低剂量顺铂通过 CEBPB 转录下调 CBX4。此外，CBX4 通过诱导 K97 和 K280 处的 SUMO1 修饰，竞争性抑制 YAP1-S127 磷酸化，从而保留了 Hippo 通路关键参与者 YAP1 的稳定性和细胞质核转运。我们的研究强调了 CBX4 的抗衰老作用，并表明 CBX4 抑制与低剂量顺铂联合有可能克服化疗耐药性并有效限制 GC 进展。