Low levels of AMPK promote epithelial‐mesenchymal transition in lung cancer primarily through HDAC4‐ and HDAC5‐mediated metabolic reprogramming

Abstract

AMP‐activated protein kinase (AMPK) serves as a “supermetabolic regulator” that helps maintain cellular energy homeostasis. However, the role of AMPK in glucose metabolism reprogramming in lung cancer remains unclear. Here, our study shows that low AMPK expression correlates with metastasis and clinicopathologic parameters of non–small‐cell lung cancer. Low AMPK significantly enhances the Warburg effect in HBE and A549 cells, which in turn induces the expression of mesenchymal markers and enhances their invasion and migration. At the mechanistic level, low AMPK up‐regulates HK2 expression and glycolysis levels through HDAC4 and HDAC5. Collectively, our findings demonstrate that low AMPK‐induced metabolism can promote epithelial‐mesenchymal transition progression in normal bronchial epithelial cells and lung cancer cells, and increase the risk for tumour metastasis.

The Epithelial–Mesenchymal Transition at the Crossroads between Metabolism and Tumor Progression

“…Interestingly, low AMPK expression levels correlate with tumor grade, TNM stage, and lymph node metastasis. Low AMPK levels in human bronchial epithelial HBE cells are responsible for an increase in glycolytic flux (due to the induction of HK2 expression which, in turn, promotes EMT ( Figure 3 ) [ 170 ]. AMPK ↓ ⇒ HK2 ↑ ⇒ Glycolysis ↑ ⇒ EMT …”

Insights Into the Function and Clinical Application of HDAC5 in Cancer Management

“…As dysregulation of energy metabolism also contributes to EMT ( 76 ), it is possible that metabolic reprogramming is involved in HDAC5-mediated EMT. It was recently demonstrated that HDAC5 together with HDAC4 enhanced glycolysis by inducing the upregulation of hexokinase 2 (HK2), which was critical for EMT induced by hypoexpression of 5′ AMP-activated protein kinase (AMPK) in lung cancer ( 72 ).…”

Novel long non‐coding RNA CYB561‐5 promotes aerobic glycolysis and tumorigenesis by interacting with basigin in non‐small cell lung cancer

“…Cell proliferation ability was determined using a Cell Counting Kit‐8 (CCK‐8; KeyGen Biotech) and a colony formation assay as previously reported 19 . Briefly, 5 × 10 3 cells were seeded in 96‐well plates, and recommended volume of CCK‐8 solution was added at 24, 48, 72 and 96 h, respectively.…”

“…The migration and invasion assays were performed as previously described 19 . For the migration assay, 4 × 10 4 H1299 cells or H292 cells were seeded in serum‐free medium in the upper chamber and incubated for 24 h at 37℃.…”