Dipartimento di Biologia e Patologia Cellulare e Molecolare c/o Istituto di Endocrinologia ed Oncologia Sperimentale del CNR, Facoltà di Medicina e Chirurgia di Napoli, Università degli Studi di Napoli Federico II, Naples, Italy.
Oncogene. 2011 Jul 7;30(27):3024-35. doi: 10.1038/onc.2011.21. Epub 2011 Feb 21.
DNA-damaging therapies represent a keystone in cancer treatment. Unfortunately, many tumors often relapse because of a group of cancer cells, which are resistant to conventional therapies. High-mobility group A (HMGA) proteins has a key role in cell transformation, and their overexpression is a common feature of human malignant neoplasias, representing a poor prognostic index often correlated to anti-cancer drug resistance. Our previous results demonstrated that HMGA1 is a substrate of ataxia-telangiectasia mutated (ATM), the main cellular sensor of genotoxic stress. Here we also report thatHMGA2, the other member of the HMGA family, is a novel substrate of ATM. Interestingly, we found that HMGA proteins positively regulate ATM gene expression. Moreover, induction of ATM kinase activity by DNA-damaging agents enhances HMGA-dependent transcriptional activation of ATM promoter, suggesting that ATM expression is modulated by a DNA-damage- and HMGA-dependent positive feedback loop. Finally, inhibition of HMGA expression in mouse embryonic fibroblasts and in cancer cells strongly reduces ATM protein levels, impairing the cellular DNA-damage response and enhancing the sensitivity to DNA-damaging agents. These findings indicate this novel HMGA-ATM pathway as a new potential target to improve the effectiveness of conventional anti-neoplastic treatments on the genotoxic-drug resistant cancer cells.
DNA 损伤疗法是癌症治疗的基石。不幸的是，许多肿瘤经常复发，因为一组对常规疗法有抗性的癌细胞。高迁移率族 A（HMGA）蛋白在细胞转化中起着关键作用，其过表达是人类恶性肿瘤的一个常见特征，代表着预后不良的指标，通常与抗癌药物耐药性相关。我们之前的研究结果表明，HMGA1 是共济失调毛细血管扩张突变（ATM）的底物，ATM 是细胞对遗传毒性应激的主要传感器。在这里，我们还报告 HMGA2，HMGA 家族的另一个成员，是 ATM 的一个新的底物。有趣的是，我们发现 HMGA 蛋白正向调节 ATM 基因的表达。此外，DNA 损伤剂诱导 ATM 激酶活性增强了 HMGA 依赖的 ATM 启动子转录激活，表明 ATM 表达受 DNA 损伤和 HMGA 依赖的正反馈回路调节。最后，在小鼠胚胎成纤维细胞和癌细胞中抑制 HMGA 的表达强烈降低了 ATM 蛋白水平，损害了细胞的 DNA 损伤反应，并增强了对 DNA 损伤剂的敏感性。这些发现表明，这种新型的 HMGA-ATM 途径是提高传统抗肿瘤治疗对遗传毒性耐药癌细胞有效性的一个新的潜在靶点。
