CUL4B Promotes Temozolomide Resistance in Gliomas by Epigenetically Repressing CDNK1A Transcription.
CUL4B Promotes Temozolomide Resistance in Gliomas by Epigenetically Repressing CDNK1A Transcription.
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CUL4B 通过表观遗传抑制 CDNK1A 转录促进神经胶质瘤中的替莫唑胺耐药
DOI：
10.3389/fonc.2021.638802
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发表时间：
2021
影响因子：
4.7
通讯作者：
Gong Y
中科院分区：
文献类型：
--
作者：
Ye X;Liu X;Gao M;Gong L;Tian F;Shen Y;Hu H;Sun G;Zou Y;Gong Y
替莫唑胺（TMZ）是胶质母细胞瘤（GBM）和间变性胶质瘤的一线化疗药物，其耐药性是临床治疗的最大障碍之一。TMZ耐药性受复杂的遗传和表观遗传网络调控。了解TMZ耐药的机制有助于确定新的药物靶点和更有效的治疗方法。CUL 4 B已被证明在几种癌症类型中上调并促进进展和化疗抗性。然而，其对TMZ抗性的调节作用和机制尚未阐明。本研究的目的是阐明CUL 4 B在TMZ耐药中的作用和机制。Western blot和公开数据集分析显示，CUL 4 B在胶质瘤标本中表达上调。接受TMZ治疗的胶质瘤患者中，CUL 4 B升高与病理分期晚期、肿瘤复发、恶性分子亚型和生存率低正相关。GBM细胞系中CUL 4 B表达与TMZ耐药性相关。在GBM细胞中，敲低CUL 4 B恢复TMZ敏感性，而上调CUL 4 B促进TMZ抗性。通过衰老β-半乳糖苷酶染色、定量逆转录PCR和染色质免疫沉淀实验，我们发现CUL 4 B协同组蛋白去乙酰化酶（HDAC）共同占据CDKN 1A启动子，表观遗传上沉默CDKN 1A的转录，从而减弱TMZ诱导的GBM细胞衰老，使其产生TMZ抗性。总的来说，我们的研究结果确定了GBM细胞对TMZ产生耐药性的新机制，并表明CUL 4 B抑制可能有利于克服耐药性。
Resistance to temozolomide (TMZ), the first-line chemotherapeutic drug for glioblastoma (GBM) and anaplastic gliomas, is one of the most significant obstacles in clinical treatment. TMZ resistance is regulated by complex genetic and epigenetic networks. Understanding the mechanisms of TMZ resistance can help to identify novel drug targets and more effective therapies. CUL4B has been shown to be upregulated and promotes progression and chemoresistance in several cancer types. However, its regulatory effect and mechanisms on TMZ resistance have not been elucidated. The aim of this study was to decipher the role and mechanism of CUL4B in TMZ resistance. Western blot and public datasets analysis showed that CUL4B was upregulated in glioma specimens. CUL4B elevation positively correlated with advanced pathological stage, tumor recurrence, malignant molecular subtype and poor survival in glioma patients receiving TMZ treatment. CUL4B expression was correlated with TMZ resistance in GBM cell lines. Knocking down CUL4B restored TMZ sensitivity, while upregulation of CUL4B promoted TMZ resistance in GBM cells. By employing senescence β-galactosidase staining, quantitative reverse transcription PCR and Chromatin immunoprecipitation experiments, we found that CUL4B coordinated histone deacetylase (HDAC) to co-occupy the CDKN1A promoter and epigenetically silenced CDKN1A transcription, leading to attenuation of TMZ-induced senescence and rendering the GBM cells TMZ resistance. Collectively, our findings identify a novel mechanism by which GBM cells develop resistance to TMZ and suggest that CUL4B inhibition may be beneficial for overcoming resistance.
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影响因子：
78.5
作者：
Collado, Manuel;Serrano, Manuel
通讯作者：
Serrano, Manuel
影响因子：
14
作者：
Truong D;Fiorelli R;Barrientos ES;Melendez EL;Sanai N;Mehta S;Nikkhah M
通讯作者：
Nikkhah M
DOI：
10.1073/pnas.92.20.9363
发表时间：
1995-09-26
影响因子：
11.1
作者：
DIMRI, GP;LEE, XH;CAMPISI, J
通讯作者：
CAMPISI, J
影响因子：
8.8
作者：
Haugstetter, A. M.;Loddenkemper, C.;Lenze, D.;Groene, J.;Standfuss, C.;Petersen, I.;Doerken, B.;Schmitt, C. A.
通讯作者：
Schmitt, C. A.
影响因子：
8.8
作者：
Günther, W;Pawlak, E;Damasceno, R;Arnold, H;Terzis, AJ
通讯作者：
Terzis, AJ