TERT promoter mutations occur in the majority of glioblastoma, bladder cancer (BC), and other malignancies while the ETS family transcription factors GABPA and its partner GABPB1 activate the mutant TERT promoter and telomerase in these tumors. GABPA depletion or the disruption of the GABPA/GABPB1 complex by knocking down GABPB1 was shown to inhibit telomerase, thereby eliminating the tumorigenic potential of glioblastoma cells. GABPA/B1 is thus suggested as a cancer therapeutic target. However, it is unclear about its role in BC. Here we unexpectedly observed that GABPA ablation inhibited TERT expression, but robustly increased proliferation, stem, and invasive phenotypes and cisplatin resistance in BC cells, while its overexpression exhibited opposite effects, and inhibited in vivo metastasizing in a xenograft transplant model. Mechanistically, GABPA directly activates the transcription of FoxA1 and GATA3, key transcription factors driving luminal differentiation of urothelial cells. Consistently, TCGA/GEO dataset analyses show that GABPA expression is correlated positively with luminal while negatively with basal signatures. Luminal tumors express higher GABPA than do basal ones. Lower GABPA expression is associated with the GABPA gene methylation or deletion (especially in basal subtype of BC tumors), and predicted significantly shorter patient survival based on TCGA and our cohort of BC patient analyses. Taken together, GABPA dictates luminal identity of BC cells and inhibits aggressive diseases in BC by promoting cellular differentiation despite its stimulatory effect on telomerase/TERT activation. Given these biological functions and its frequent methylation and/or deletion, GABPA serves as a tumor suppressor rather than oncogenic factor in BC. The GABPA effect on oncogenesis is context-dependent and its targeting for telomerase inhibition in BC may promote disease metastasizing.

中文翻译：

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GABPA 是管腔特性的主要调节因子，可抑制膀胱癌的侵袭性疾病。

TERT 启动子突变发生在大多数胶质母细胞瘤、膀胱癌 (BC) 和其他恶性肿瘤中，而 ETS 家族转录因子 GABPA 及其伴侣 GABPB1 会激活这些肿瘤中的突变 TERT 启动子和端粒酶。研究表明，GABPA 耗竭或通过敲低 GABPB1 来破坏 GABPA/GABPB1 复合物可以抑制端粒酶，从而消除胶质母细胞瘤细胞的致瘤潜力。因此，GABPA/B1 被建议作为癌症治疗靶点。然而，其在 BC 中的作用尚不清楚。在这里，我们出乎意料地观察到，GABPA 消除抑制了 TERT 表达，但在 BC 细胞中显着增加了增殖、干细胞和侵袭表型以及顺铂耐药性，而其过表达则表现出相反的效果，并在异种移植模型中抑制了体内转移。从机制上讲，GABPA 直接激活 FoxA1 和 GATA3 的转录，这是驱动尿路上皮细胞管腔分化的关键转录因子。TCGA/GEO 数据集分析一致表明，GABPA 表达与管腔呈正相关，而与基础特征呈负相关。管腔肿瘤比基底肿瘤表达更高的 GABPA。较低的 GABPA 表达与 GABPA 基因甲基化或缺失相关（尤其是在 BC 肿瘤的基础亚型中），并且根据 TCGA 和我们的 BC 患者队列分析预测患者生存期显着缩短。总而言之，GABPA 决定了 BC 细胞的管腔特性，并通过促进细胞分化来抑制 BC 中的侵袭性疾病，尽管它对端粒酶/TERT 激活有刺激作用。鉴于这些生物学功能及其频繁的甲基化和/或缺失，GABPA 在 BC 中充当肿瘤抑制因子而不是致癌因子。GABPA 对肿瘤发生的影响是上下文相关的，其针对 BC 中端粒酶抑制的作用可能会促进疾病转移。