Long noncoding RNAs (lncRNAs) contribute to esophageal squamous cell carcinoma (ESCC) progression, but the underlying mechanisms remain elusive. In this study, we verified a hitherto uncharacterized hypoxia-responsive lncRNA, G077640, which is upregulated in human ESCC cells and tissues, supporting the proliferation and migration of ESCC cells. Mechanistically, G077640 prevented hypoxia-inducible factor-1α (HIF1α) from being degraded by directly interacting with histone H2AX and further modulated the interaction of HIF1α and H2AX. In addition, G077640 reprogrammed glycolytic metabolism by regulating the expression of glucose transporter 4 (GLUT4), hexokinase 2 (HK2) and pyruvate dehydrogenase kinase 1 (PDK1) for ESCC proliferation and migration. Clinically, G077640 was associated with poor prognosis in ESCC patients. Taken together, our findings identified a hypoxia-responsive lncRNA that contributes to ESCC cells proliferation and migration, and targeting G077640 and its pathway might be a potential therapeutic strategy for ESCC.

中文翻译：

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缺氧反应性 lncRNA G077640 通过 H2AX-HIF1α-糖酵解轴促进 ESCC 肿瘤发生。

长非编码 RNA (lncRNA) 有助于食管鳞状细胞癌 (ESCC) 的进展，但其潜在机制仍不清楚。在这项研究中，我们验证了一种迄今为止尚未表征的缺氧反应性lncRNA G077640，它在人食管鳞癌细胞和组织中表达上调，支持食管鳞癌细胞的增殖和迁移。从机制上讲，G077640 通过与组蛋白 H2AX 直接相互作用来防止缺氧诱导因子 1α (HIF1α) 降解，并进一步调节 HIF1α 和 H2AX 的相互作用。此外，G077640 通过调节葡萄糖转运蛋白 4 (GLUT4)、己糖激酶 2 (HK2) 和丙酮酸脱氢酶激酶 1 (PDK1) 的表达来重新编程糖酵解代谢，从而促进 ESCC 增殖和迁移。临床上，G077640 与 ESCC 患者的不良预后相关。综上所述，我们的研究结果确定了一种缺氧反应性 lncRNA，有助于 ESCC 细胞的增殖和迁移，而靶向 G077640 及其通路可能是 ESCC 的潜在治疗策略。