Jung Megan, Bui Indy, Bonavida Benjamin
Department of Microbiology, Immunology & Molecular Genetics, David Geffen School of Medicine, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90095, USA.
Cancers (Basel). 2023 Aug 25;15(17):4267. doi: 10.3390/cancers15174267.
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.
癌症是人类所患各种疾病中主要的死亡原因之一。癌症并非单一实体，而是由众多不同类型和亚型组成，需要采用各种治疗方案。在过去十年中，癌症治疗取得了几个里程碑式的进展，比如特异性靶向药物或激活休眠的抗肿瘤免疫反应。这些里程碑式进展带来了显著的积极临床反应、肿瘤消退以及部分癌症患者生存期的延长。因此，在无反应患者和复发无反应患者中，癌症通过抗凋亡基因产物的过表达形成了对细胞死亡的内在抗性机制。与此同时，据报道大多数耐药癌症会过表达一种转录因子——阴阳1（YY1），它可调节癌细胞对治疗性抗癌细胞毒性药物的化学免疫抗性。本文研究了YY1过表达与几种抗凋亡基因产物之间的关系，这些抗凋亡基因产物包括B细胞淋巴瘤2蛋白（Bcl-2）、Bcl-2相关X蛋白（Bcl-xL）、髓样细胞白血病序列1（Mcl-1）和生存素。研究结果表明，这些抗凋亡基因产物在转录、表观遗传、转录后和翻译水平上部分受YY1调控。虽然针对每种抗凋亡基因产物进行单独靶向研究并在临床上进行了一些测试，但由于其他过表达的抗凋亡基因产物的补偿作用，这种靶向策略并不有效。相比之下，通过小分子干扰RNA（siRNA）、基因编辑或小分子抑制剂直接靶向YY1，在YY1过表达的耐药癌症中可能在治疗上更有效且具有普遍性。
