Hypoxia-induced SZT2-AS1 is required for HIF-1 heterodimer formation and histone trimethylation in HCC cells under hypoxic microenvironment

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 they coordinate the process of hypoxia-induced gene expression leading to cancer progression. Increasing evidence has indicated 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 a novel lncRNA SZT2-AS1 in HCC, which was induced by hypoxia in a HIF-1-dependent manner and promoted HCC growth, metastasis and angiogenesis. The clinical data indicated that SZT2-AS1 level was substantially upregulated in HCC and significantly associated with poor clinical outcomes, and acted as an independent prognostic predictor. Mechanistically, SZT2-AS1, in turn, recruited HIF-1α and HIF-1β to form the HIF-1 heterodimer. And SZT2-AS1 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 modification 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 potential therapeutic strategy for HCC. Significance: LncRNA SZT2-AS1 involves in a positive feedback mechanism under hypoxia, which provides a therapeutic strategy for HCC.