A Novel Hypoxia-induced LncRNA, SZT2-AS1, Boosts HCC Progression by Mediating HIF Heterodimerization and Histone Trimethylation Under a Hypoxic Microenvironment

Overview

Journal Cell Death Differ

Specialty Cell Biology

Date 2024 Nov 21

PMID 39572656

Authors

Runkun Liu

Yixian Guo

Liang Wang

Guozhi Yin

Hang Tuo

Yifeng Zhu

Wei Yang

Qingguang Liu

Yufeng Wang

Affiliations

Soon will be listed here.

Abstract

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.

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