Hypoxia upregulates Malat1 expression through a CaMKK/AMPK/HIF-1α axis

Abstract

Increased expression levels of the long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (Malat1) have been associated with enhanced proliferation and metastasis of several cancer cell types. Hypoxia, a hallmark characteristic of solid tumors, has been linked to an increase in the activity of the ATP-generating AMPK protein. Since Malat1 was recently shown to be upregulated during hypoxia, the objective of this study was to determine the contribution of AMPK in the mechanistic pathways regulating Malat1 expression in low oxygen conditions. Compared to those cultured in 21% O2 conditions, HeLa cells incubated in 1.5% O2 expressed more Malat1 transcripts. This observation was mimicked in HEK293T cells using a synthetic reporter construct containing 5.6 kb of the human Malat1 promoter, suggesting that hypoxia directly impacted Malat1 gene transcription. Interestingly, pharmacological stimulation of AMPK increased Malat1 promoter transactivation in 21% O2 conditions, whereas inhibition of either AMPK or its upstream activator CaMKK completely abolished the augmentation of Malat1 under hypoxia. Pharmacological modulation of LKB1, another major regulator of AMPK, had no impact on Malat1 promoter transactivation, suggesting that calcium inputs are important in the control of Malat1 expression by AMPK. Overexpression of hypoxia-inducible factor-1α (HIF-1α) increased Malat1 expression in 21% O2 conditions, whereas pharmacological inhibition of HIF-1α blocked the impact of hypoxia on the Malat1 promoter. Taken together, these findings strongly suggest that Malat1 expression is regulated in hypoxic conditions by a CaMKK/AMPK/HIF-1α axis. More research is needed in physiological settings to test the clinical relevance of this pathway.

Long non‐coding RNA MALAT1 mediates hypoxia‐induced pro‐survival autophagy of endometrial stromal cells in endometriosis

“…More importantly, previous studies reported that hypoxia provides an important driving factor in the expression pattern of various lncRNAs including MALAT1. For example, Sallé‐Lefort et al demonstrated lncRNA‐MALAT1 expression is regulated in hypoxic conditions by a CaMKK/AMPK/HIF‐1α axis . In another study, Brock et al found that the levels of lncRNA‐MALAT1 were significantly increased in hypoxic human pulmonary artery smooth muscle .…”

AMPK: guardian of metabolism and mitochondrial homeostasis

“…This has been shown to have a role particularly in response to hormones and stresses that acutely control intracellular calcium, including processes such as the regulation of food intake by hypothalamic neurons in mice 70,71 , activation of antigen and thrombin receptors in immune and endothelial cells, respectively 72,73 , and stimulation of mitochondrial activity by thyroid hormone 74,75 . Notably, CAMKK2 has also been shown to activate AMPK following cellular stresses, including amino acid starvation 76 , hypoxia 77,78 and cell detachment from the matrix 79 . In LKB1-null cells, CAMKK2 is able to maintain some AMPK activity that is still sensitive to changes in the ATP-to-AMP ratio 80 .…”

Autophagy stimulation and intracellular sodium reduction as mediators of the cardioprotective effect of sodium–glucose cotransporter 2 inhibitors

“…AMPK is a critical energy sensor that discerns the balance between ATP and AMP in the cytosol; SIRT1 is a redox‐sensing nicotinamide adenine dinucleotide‐dependent enzyme that deacetylates target proteins that play important roles in the regulation of cellular processes involved in metabolism and homeostasis; and HIF‐1α activates the transcription of genes that promote oxygen delivery and reduce oxygen utilization, switching cells from oxidative to glycolytic metabolism . These three molecules interact with, reinforce and regulate each other and share common targets . Additionally, SIRT1 appears to induce HIF‐2α, which may also promote autophagic clearance of damaged organelles .…”