HIF is a nuclear transcription factor that is produced by cancer cells adapting to hypoxic environments [
54]. Activation of HIF-1α contributes to Warburg effect, partly through the upregulation of GLUTs, thereby increasing glucose uptake [
55] or by increasing the expression of glycolytic enzymes [
56,
57] or by inhibiting oxidative phosphorylation [
58]. These studies indicate that the Warburg effect is not caused just by hypoxia, but rather through a more specific regulation of transcription, in which HIF-1 increases the expression of most glycolytic enzymes.
Hypoxia is thought to be related to Warburg effect, although the underlying mechanism is not yet clear. LincRNA-p21 was originally thought to be a p53-induced lncRNA that regulated P53-triggered apoptosis in murine models [
59]. However, it is not associated with apoptosis in human tissues. LincRNA-p21 is a hypoxia-responsive lincRNA that competes with HIF-1α to bind to the von Hippel-Lindau tumor suppressor protein (pVHL) and prevents the formation of HIF-1α-pVHL, thus inhibiting the ubiquitinated degradation of HIF-1α. pVHL is a component of ubiquitin ligase complex that binds to HIF-1α and routes it to the proteasome degradation pathway. Thus, lincRNA-p21 plays an important role in hypoxia-induced glycolysis. Under hypoxic conditions, HIF-1α-induced lincRNA-p21 stabilizes HIF-1α, forming a positive feedback loop. But this loop is not always activated because hypoxic stimulation may slow down [
60]. In human hepatic epithelial cells (L-02), arsenite increases the expression of glycolysis-related genes, including HK2, Eno-1, and Glut-4. In L-02 cells exposed to arsenite, the lncRNA, metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), and HIF-α, are overexpressed. Moreover, MALAT1 enhances arsenite-induced glycolysis by promoting the disassociation of HIF-1α from VHL, preventing VHL-mediated ubiquitination of HIF-1α, which causes the accumulation of HIF-1α [
61]. However, the overexpression of lncRNA-LET results in a decrease in the expression of HIF-1α [
62]. Hypoxia also induces LncRNA H19, which is involved in hypoxia-induced signal transduction processes in cancer cells, thereby altering glucose metabolism [
63]. Lin reported that an lncRNA in cytoplasm, long intergenic non-coding RNA for kinase activation (LINK-A), is involved in the metabolic reprogramming in triple-negative breast cancer [
64]. LINK-A facilitates the recruitment of BRK to the EGFR-GPNMB complex and activates BRK kinase. The BRK-dependent phosphorylation of HIF1α at tyrosine 565 interferes with hydroxylation of proline 564, thereby stabilizing HIF1α. LINK-A promotes the metabolic reprogramming and tumor progression in triple negative breast cancer by activating HIF1α. Takahashi et al. reported that linc-ROR is associated with hypoxia response and can act as a molecular sponge of miR-145 to regulate HIF-1α and its target genes such as VEGF, TGF-β, and PDK1 [
65] (Fig.
2).