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Abstract Hypoxia is an important feature of the tumor microenvironment (TME). While targeting hypoxic TME is emerging as a potential strategy for treating solid tumors including liver cancer. Recent studies have shown that hypoxia can regulate tumor adaptation to hypoxic TME through long non-coding RNA (lncRNA). In the previous study, we identify a novel hypoxia-activated lncRNA and termed it as HABON. Here, we demonstrated that knockdown of HABON caused necroptosis of tumor tissue and inhibited the subcutaneous tumor growth of SMMC-7721 cells in nude mice. Moreover, knockdown of HABON increased RIPK1 and MLKL expression as well as their phosphorylation level in SMMC-7721 and Huh7 liver cancer cells. Meanwhile, Necrostatin-1 and GSK872 could restore cell death of liver cancer cells caused by knockdown of HABON under hypoxia. The above results suggested that HABON could inhibit hypoxia-induced necroptosis of liver cancer cells. Mechanically, knockdown of HABON in liver cancer cells aggravated mitochondrial dysfunction caused by hypoxia. Furthermore, the RNA pull-down combined with mass spectrometry analysis identified HABON can interact with mitochondria-related protein VDAC1 and the RNA immunoprecipitation (RIP) analysis proved the interaction. In addition, we proved that VDAC1 mediated the mitochondrial permeability transition pore (mPTP) opening, mitochondrial dysfunction, as well as necroptosis caused by knockdown of HABON. Overall, our work demonstrates HABON can reduce hypoxia-induced necroptosis of liver cancer cells and suggests that inhibition of HABON in the hypoxic TME is a potential therapeutic strategy for treating liver cancer.

Multiple myeloma is a malignant plasma-cell disease, which is highly dependent on the hypoxic bone marrow microenvironment. However, the underlying mechanisms of hypoxia contributing to myeloma genesis are not fully understood. Here, we show that long non-coding RNA DARS-AS1 in myeloma is directly upregulated by hypoxia inducible factor (HIF)-1. Importantly, DARS-AS1 is required for the survival and tumorigenesis of myeloma cells both in vitro and in vivo. DARS-AS1 exerts its function by binding RNA-binding motif protein 39 (RBM39), which impedes the interaction between RBM39 and its E3 ubiquitin ligase RNF147, and prevents RBM39 from degradation. The overexpression of RBM39 observed in myeloma cells is associated with poor prognosis. Furthermore, knockdown of DARS-AS1 inhibits the mammalian target of rapamycin signaling pathway, an effect that is reversed by RBM39 overexpression. We reveal that a novel HIF-1/DARS-AS1/RBM39 pathway is implicated in the pathogenesis of myeloma. Targeting DARS-AS1/RBM39 may, therefore, represent a novel strategy to combat myeloma.