Cancer is a leading cause of death among the various diseases encountered in humans. Cancer is not a single entity and consists of numerous different types and subtypes that require various treatment regimens. In the last decade, several milestones in cancer treatments were accomplished, such as specific targeting agents or revitalizing the dormant anti-tumor immune response. These milestones have resulted in significant positive clinical responses as well as tumor regression and the prolongation of survival in subsets of cancer patients. Hence, in non-responding patients and non-responding relapsed patients, cancers develop intrinsic mechanisms of resistance to cell death via the overexpression of anti-apoptotic gene products. In parallel, the majority of resistant cancers have been reported to overexpress a transcription factor, Yin Yang 1 (YY1), which regulates the chemo-immuno-resistance of cancer cells to therapeutic anticancer cytotoxic agents. The relationship between the overexpression of YY1 and several anti-apoptotic gene products, such as B-cell lymphoma 2 protein (Bcl-2), B-cell lymphoma extra-large (Bcl-xL), myeloid cell leukemia 1 (Mcl-1) and survivin, is investigated in this paper. The findings demonstrate that these anti-apoptotic gene products are regulated, in part, by YY1 at the transcriptional, epigenetic, post-transcriptional and translational levels. While targeting each of the anti-apoptotic gene products individually has been examined and clinically tested for some, this targeting strategy is not effective due to compensation by other overexpressed anti-apoptotic gene products. In contrast, targeting YY1 directly, through small interfering RNAs (siRNAs), gene editing or small molecule inhibitors, can be therapeutically more effective and generalized in YY1-overexpressed resistant cancers.
在人类面临的众多疾病中，癌症是导致死亡的主要原因之一。癌症并非单一疾病，而是包含众多不同类型和亚型，需要采取多种治疗方案。过去十年间，癌症治疗领域取得了多项里程碑式进展，例如特异性靶向药物的应用以及重新激活休眠的抗肿瘤免疫反应。这些进展显著改善了部分癌症患者的临床疗效，实现了肿瘤消退并延长了生存期。然而，在无应答患者及复发无应答患者中，癌细胞通过过度表达抗凋亡基因产物，形成了抵抗细胞死亡的内在机制。与此同时，研究表明多数耐药性癌症会过度表达一种转录因子——阴阳1（YY1），该因子调控着癌细胞对治疗性抗癌细胞毒药物的化学免疫耐药性。本文探讨了YY1过度表达与多种抗凋亡基因产物之间的关系，包括B细胞淋巴瘤2蛋白（Bcl-2）、B细胞淋巴瘤超大蛋白（Bcl-xL）、髓样细胞白血病1（Mcl-1）以及存活蛋白。研究结果表明，这些抗凋亡基因产物在转录、表观遗传、转录后及翻译水平上均受到YY1的部分调控。尽管针对单个抗凋亡基因产物的靶向策略已得到部分研究和临床验证，但由于其他过度表达的抗凋亡基因产物会产生代偿效应，这种靶向策略效果有限。相比之下，通过小干扰RNA（siRNAs）、基因编辑或小分子抑制剂直接靶向YY1，在YY1过度表达的耐药性癌症中可能具有更广泛且有效的治疗前景。
Role of YY1 in the Regulation of Anti-Apoptotic Gene Products in Drug-Resistant Cancer Cells
肿瘤(癌症)患者之家