Hypoxic microenvironment plays a critical role in solid tumor growth, metastasis and angiogenesis. Hypoxia-inducible factors (HIFs), which are canonical transcription factors in response to hypoxia, are stabilized under hypoxia and coordinate the process of hypoxia-induced gene expression, leading to cancer progression. Increasing evidence has uncovered that long noncoding RNAs (lncRNAs), which are closely associated with cancer, play crucial roles in hypoxia-mediated HCC progression, while the mechanisms are largely unknown. Here, we identified SZT2-AS1 as a novel lncRNA in HCC, which was induced by hypoxia in a HIF-1-dependent manner and promoted HCC growth, metastasis and angiogenesis both in vitro and in vivo. And SZT2-AS1 also mediated the hypoxia-induced HCC progression. Clinical data indicated that SZT2-AS1 level was substantially increased in HCC and closely associated with poor clinical outcomes, acting as an independent prognostic predictor. Mechanistically, SZT2-AS1 recruited HIF-1α and HIF-1β to form the HIF-1 heterodimer, and it was required for the occupancy of HIF-1 to hypoxia response elements (HREs) and HIF target gene transcription. In addition, SZT2-AS1 was required for hypoxia-induced histone trimethylation (H3K4me3 and H3K36me3) at HREs. Through recruiting methyltransferase SMYD2, SZT2-AS1 promoted trimethylation of H3K4 and H3K36 in HCC cells. Taken together, our results uncovered a lncRNA-involved positive feedback mechanism under hypoxia and established the clinical value of SZT2-AS1 in prognosis and as a potential therapeutic target in HCC.

缺氧微环境在实体瘤生长、转移和血管生成中起关键作用。缺氧诱导因子 （HIF） 是响应缺氧的经典转录因子，在缺氧下稳定并协调缺氧诱导的基因表达过程，导致癌症进展。越来越多的证据表明，与癌症密切相关的长链非编码 RNA （lncRNA） 在缺氧介导的 HCC 进展中起着关键作用，而其机制在很大程度上是未知的。在这里，我们将 SZT2-AS1 鉴定为 HCC 中的一种新型 lncRNA，它由缺氧以 HIF-1 依赖性方式诱导，并在体外和体内促进 HCC 生长、转移和血管生成。SZT2-AS1 还介导缺氧诱导的 HCC 进展。临床数据表明，SZT2-AS1 水平在 HCC 中显著升高，与不良临床结局密切相关，是独立的预后预测因子。从机制上讲，SZT2-AS1 募集 HIF-1α 和 HIF-1β 形成 HIF-1 异二聚体，并且 HIF-1 对缺氧反应元件 （HRE） 和 HIF 靶基因转录的占据是必需的。此外，SZT2-AS1 是缺氧诱导的组蛋白三甲基化 （H3K4me3 和 H3K36me3） 在 SRE 上所必需的。SZT2-AS1 通过募集甲基转移酶 SMYD2 促进 HCC 细胞中 H3K4 和 H3K36 的三甲基化。综上所述，我们的结果揭示了缺氧下 lncRNA 参与的正反馈机制，并确定了 SZT2-AS1 在预后中的临床价值以及作为 HCC 的潜在治疗靶点。