HADHA 通过加速 MDM2 介导的 p53 泛素化来促进神经胶质瘤进展。
HADHA promotes glioma progression by accelerating MDM2-mediated p53 ubiquitination.
发表日期:2024 Jul 22
作者:
Rudong Chen, Hao Chen, Changchen Hu
来源:
CANCER GENE THERAPY
摘要:
胶质瘤是一种众所周知的侵袭性恶性肿瘤,针对中枢神经系统,患者预后较差。在这项研究中,我们着手研究羟酰辅酶A脱氢酶三功能多酶复合物α亚基(HADHA)在神经胶质瘤中的作用、其临床意义及其潜在的生物学机制。在本研究中,我们使用免疫组织化学染色来评估胶质瘤组织中 HADHA 的表达水平。我们还使用 Kaplan-Meier 方法评估了 HADHA 表达与患者生存之间的相关性。为了确定 HADHA 在神经胶质瘤细胞中的作用,我们进行了体外和体内功能丧失测定。此外,我们利用免疫共沉淀和蛋白质稳定性测定来研究神经胶质瘤中涉及 HADHA、MDM2 和 p53 的潜在机制。我们的研究结果表明神经胶质瘤表现出高水平的 HADHA。临床上,HADHA的高表达表明恶性肿瘤、复发的风险增加,生存率降低。从功能上来说,敲除 HADHA 可以导致神经胶质瘤细胞增殖减少、细胞凋亡增强并抑制迁移。从机制上讲,HADHA 通过与 MDM2 相互作用加速 MDM2 介导的 p53 泛素化。一致地,MDM2敲低或p53过表达可以减弱HADHA过表达对胶质瘤恶性进展的促进作用。我们发现 HADHA 在促进 MDM2 介导的 p53 泛素化方面的新作用,这有助于神经胶质瘤的进展。这一发现为理解神经胶质瘤的发病机制提供了新的视角,并为开发创新治疗策略提供了潜在的目标。© 2024。作者,获得 Springer Nature America, Inc. 的独家许可。
Glioma represents a notoriously aggressive and malignant tumor that targets the central nervous system, with a poor prognosis for patients. In this research, we set out to examine the role of hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit alpha (HADHA) in glioma, its clinical significance, as well as its potential biological mechanisms. In this study, we used immunohistochemistry staining to assess the expression level of HADHA in glioma tissues. We also evaluated the correlation between HADHA expression and patient survival using the Kaplan-Meier method. To determine the role of HADHA in glioma cells, we conducted loss-of-function assays in vitro and in vivo. Additionally, we utilized co-immunoprecipitation and protein stability assays to investigate the potential mechanisms involving HADHA, MDM2, and p53 in glioma. Our research findings indicate that gliomas exhibit high levels of HADHA. Clinically, high expression of HADHA suggests an increased risk of malignant tumors, recurrence, and reduced survival rates. Functionally, knocking down HADHA can lead to decreased proliferation, enhanced apoptosis, and inhibited migration of glioma cells. Mechanistically, HADHA accelerates MDM2-mediated p53 ubiquitination through interaction with MDM2. Consistently, MDM2 knockdown or overexpression of p53 can attenuate the promoting effect of HADHA overexpression on the malignant progression of glioma. We have discovered a novel role of HADHA in promoting MDM2-mediated p53 ubiquitination, which contributes to the progression of glioma. This finding provides a new perspective to understand the pathogenesis of glioma and offers a potential target for developing innovative therapeutic strategies.© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.