CBX4 通过诱导 YAP1 SUMOylation 抵消细胞衰老,使胃癌细胞对化疗不再敏感

IF 15.8 1区 医学 Q1 PHARMACOLOGY & PHARMACY
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引用次数: 0

摘要

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深入,细胞衰老的治疗潜力也日益得到认可。在这里,我们确定了小泛素相关修饰物(SUMO)E3 连接酶 chromobox 4(CBX4)是细胞衰老的拮抗剂,并阐明了 CBX4 促进胃癌(GC)耐药性和恶性进展的新机制。方法通过体外和体内模型研究 CBX4 对细胞衰老和化疗耐药性的表现和影响。结果CBX4通过使衰老相关的Hippo通路失活,降低了GC细胞对细胞衰老的敏感性,促进了化疗抗性和GC的发展。从机理上讲,低剂量顺铂可通过 CEBPB 转录下调 CBX4。此外,CBX4 通过诱导 K97 和 K280 处的 SUMO1 修饰,竞争性地抑制 YAP1-S127 磷酸化,从而保护了 Hippo 通路的关键角色 YAP1 的稳定性和胞质-核转运。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
CBX4 counteracts cellular senescence to desensitize gastric cancer cells to chemotherapy by inducing YAP1 SUMOylation

Aims

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.

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来源期刊
Drug Resistance Updates
Drug Resistance Updates 医学-药学
CiteScore
26.20
自引率
11.90%
发文量
32
审稿时长
29 days
期刊介绍: Drug Resistance Updates serves as a platform for publishing original research, commentary, and expert reviews on significant advancements in drug resistance related to infectious diseases and cancer. It encompasses diverse disciplines such as molecular biology, biochemistry, cell biology, pharmacology, microbiology, preclinical therapeutics, oncology, and clinical medicine. The journal addresses both basic research and clinical aspects of drug resistance, providing insights into novel drugs and strategies to overcome resistance. Original research articles are welcomed, and review articles are authored by leaders in the field by invitation. Articles are written by leaders in the field, in response to an invitation from the Editors, and are peer-reviewed prior to publication. Articles are clear, readable, and up-to-date, suitable for a multidisciplinary readership and include schematic diagrams and other illustrations conveying the major points of the article. The goal is to highlight recent areas of growth and put them in perspective. *Expert reviews in clinical and basic drug resistance research in oncology and infectious disease *Describes emerging technologies and therapies, particularly those that overcome drug resistance *Emphasises common themes in microbial and cancer research
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