Tumor Cell Kill by c-MYC Depletion: Role of MYC-Regulated Genes that Control DNA Double-Strand Break Repair
Tumor Cell Kill by c-MYC Depletion: Role of MYC-Regulated Genes that Control DNA Double-Strand Break Repair
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DOI：
10.1158/0008-5472.can-10-0944
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发表时间：
2010-11-01
期刊：
影响因子：
11.2
通讯作者：
Bristow, Robert G.
中科院分区：
文献类型：
--
作者：
Luoto, Kaisa R.;Meng, Alice X.;Bristow, Robert G.
MYC调节无数控制细胞增殖、代谢、分化和凋亡的基因。MYC还控制DNA双链断裂（DSB）修复基因的表达，因此可能是抗癌治疗的潜在靶点，使癌细胞对DNA损伤敏感或防止遗传不稳定。在本报告中，我们研究了MYC是否与DSB修复基因启动子结合，并在dna损伤剂的作用下调节细胞存活。染色质免疫沉淀研究表明，MYC与多种DSB修复基因启动子相关，包括Rad51、Rad51B、Rad51C、XRCC2、Rad50、BRCA1、BRCA2、DNA- pkcs、XRCC4、Ku70和DNA连接酶IV。内源性MYC蛋白表达与Rad51和Ku70蛋白表达增加有关。在G(0)-G(1)和S-G(2)-M细胞中诱导MYC导致Rad51基因表达上调。使用小干扰RNA （siRNA）敲除MYC导致RAD51表达降低，但对基于流式细胞术直接重复绿色荧光蛋白测定的同源重组的影响很小。在DU145和H1299细胞系中，siRNA对MYC以独立于凋亡的方式导致肿瘤细胞死亡。然而，myc依赖性DSB修复蛋白表达的变化不足以使细胞对丝裂霉素C或电离辐射敏感，这两种药物对DSB修复缺陷细胞有选择性毒性。我们的研究结果表明，抗myc药物可能靶向细胞以防止遗传不稳定，但不会导致不同的放射致敏或化学致敏。癌症Res;70 (21);8748 - 59。(c) 2010年aacr。
MYC regulates a myriad of genes controlling cell proliferation, metabolism, differentiation, and apoptosis. MYC also controls the expression of DNA double-strand break (DSB) repair genes and therefore may be a potential target for anticancer therapy to sensitize cancer cells to DNA damage or prevent genetic instability. In this report, we studied whether MYC binds to DSB repair gene promoters and modulates cell survival in response to DNA-damaging agents. Chromatin immunoprecipitation studies showed that MYC associates with several DSB repair gene promoters including Rad51, Rad51B, Rad51C, XRCC2, Rad50, BRCA1, BRCA2, DNA-PKcs, XRCC4, Ku70, and DNA ligase IV. Endogenous MYC protein expression was associated with increased RAD51 and KU70 protein expression of a panel of cancer cell lines of varying histopathology. Induction of MYC in G(0)-G(1) and S-G(2)-M cells resulted in upregulation of Rad51 gene expression. MYC knockdown using small interfering RNA (siRNA) led to decreased RAD51 expression but minimal effects on homologous recombination based on a flow cytometry direct repeat green fluorescent protein assay. siRNA to MYC resulted in tumor cell kill in DU145 and H1299 cell lines in a manner independent of apoptosis. However, MYC-dependent changes in DSB repair protein expression were not sufficient to sensitize cells to mitomycin C or ionizing radiation, two agents selectively toxic to DSB repair-deficient cells. Our results suggest that anti-MYC agents may target cells to prevent genetic instability but would not lead to differential radiosensitization or chemosensitization. Cancer Res; 70(21); 8748-59. (C) 2010 AACR.