目的:随着我们对细胞衰老与肿瘤生物学之间复杂关系的理解不断发展,细胞衰老的治疗潜力正在获得越来越多的认可。这里,我们识别了色框4(CBX4),一种小泛素相关修饰因子(SUMO)E3连接酶,作为细胞衰老的拮抗剂,阐明了CBX4促进胃癌(GC)耐药性和恶性进展的新机制。
方法:进行体外和体内模型以研究CBX4对细胞衰老和化学抗性的表现和影响。高通量测序,染色质免疫沉淀,和免疫共沉淀技术用于鉴定与CBX4相关的上游调节因子和下游效应因子,揭示其复杂的调节网络。
结果:CBX4降低了GC细胞对细胞衰老的敏感性,通过使衰老相关的Hippo途径失活来促进化学抗性和GC发育。机械上,低剂量顺铂通过CEBPB转录下调CBX4。此外,CBX4保留了Hippo途径的关键参与者YAP1的稳定性和细胞质-核运输,通过在K97和K280诱导SUMO1修饰,竞争性抑制YAP1-S127磷酸化。
结论: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具有克服化学耐药性并有效限制GC进展的潜力。
OBJECTIVE: 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).
METHODS: In vitro and in vivo 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.
RESULTS: 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.
CONCLUSIONS: 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.