Yin Yang 1 (YY1) is a ubiquitous transcription factor with both transcriptional activating and repressing functions. Targeting YY1 is considered as a potential therapeutic strategy for several malignancies. Telomerase Reverse Transcriptase (TERT) is also considered as a potential target for cancer therapeutics. To enable the large-scale screening and identification of potential YY1 targeting drugs, a gastric cancer cell line-based drug screening assay was developed. In a YY1 targeted drug repurpose screen, abacavir sulfate, a nucleoside analog reverse transcriptase inhibitor, known to target TERT was identified to show the feature of activating YY1 mediated transcription. We further explored i) the molecular targets of abacavir, ii) activation pattern of pathways regulated by abacavir in gastric tumors, and iii) therapeutic potential of abacavir for gastric cancer cells. Oncogenic signaling pathways like MYC, HIF1-α, ERK, WNT, E2F, NFκB and NRF1/2 were also found to be highly activated by abacavir. Abacavir was found to have less impact on the viability of gastric cancer cells. Across gastric tumors, we observed the co-activation of TERT, alternative lengthening of telomere (ALT), DNA repair, and the oncogenic pathways MYC, E2F/DP1, ERK, YY1, HIF1α, and NFκB specific gene-sets, in a subset of gastric tumors. The observed connectivity among TERT, DNA repair, and multiple oncogenic pathways indicate the need for the development of combinatorial therapeutics for the gastric tumors with the activated TERT.

中文翻译：

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阿巴卡韦在胃癌细胞中诱导YY1和其他致癌转录因子的转录活性。

阴阳1（YY1）是一种普遍存在的转录因子，具有转录激活和抑制功能。靶向YY1被认为是多种恶性肿瘤的潜在治疗策略。端粒酶逆转录酶（TERT）也被认为是癌症治疗的潜在靶标。为了能够大规模筛选和鉴定潜在的YY1靶向药物，开发了一种基于胃癌细胞系的药物筛选测定方法。在针对YY1的药物重用筛选中，确定了已知靶向TERT的核苷类似物逆转录酶抑制剂硫酸阿巴卡韦，它显示出激活YY1介导的转录的特征。我们进一步探讨了i）阿巴卡韦的分子靶标，ii）阿巴卡韦在胃肿瘤中调控的途径的激活方式，iii）阿巴卡韦对胃癌细胞的治疗潜力。阿巴卡韦也高度激活了MYC，HIF1-α，ERK，WNT，E2F，NFκB和NRF1 / 2等致癌信号通路。已发现阿巴卡韦对胃癌细胞的活力影响较小。在整个胃肿瘤中，我们观察到了TERT的共激活，端粒（ALT）的替代性延长，DNA修复以及MYC，E2F / DP1，ERK，YY1，HIF1α和NFκB特异性基因集的致癌途径。胃肿瘤。在TERT，DNA修复和多种致癌途径之间观察到的连通性表明，需要开发具有激活的TERT的胃肿瘤组合疗法。NFκB和NRF1 / 2也被阿巴卡韦高度激活。已发现阿巴卡韦对胃癌细胞的活力影响较小。在整个胃肿瘤中，我们观察到了TERT的共激活，端粒（ALT）的替代性延长，DNA修复以及MYC，E2F / DP1，ERK，YY1，HIF1α和NFκB特异性基因集的致癌途径。胃肿瘤。在TERT，DNA修复和多种致癌途径之间观察到的连通性表明，需要开发具有激活的TERT的胃肿瘤组合疗法。NFκB和NRF1 / 2也被阿巴卡韦高度激活。已发现阿巴卡韦对胃癌细胞的活力影响较小。在整个胃肿瘤中，我们观察到了TERT的共激活，端粒（ALT）的替代性延长，DNA修复以及MYC，E2F / DP1，ERK，YY1，HIF1α和NFκB特异性基因集的致癌途径。胃肿瘤。在TERT，DNA修复和多种致癌途径之间观察到的连通性表明，需要开发具有激活的TERT的胃肿瘤组合疗法。和胃癌子集中的NFκB特定基因集。在TERT，DNA修复和多种致癌途径之间观察到的连通性表明，需要开发具有激活的TERT的胃肿瘤组合疗法。和胃癌子集中的NFκB特定基因集。在TERT，DNA修复和多种致癌途径之间观察到的连通性表明，需要开发具有激活的TERT的胃肿瘤组合疗法。