Nucleus accumbens-associated protein-1 promotes glycolysis and survival of hypoxic tumor cells via the HDAC4-HIF-1α axis

Abstract

Nucleus accumbens-associated protein-1 (NAC1), a nuclear factor of the BTB/POZ gene family, has emerging roles in cancer. In this study, we identified the NAC1-HDAC4-HIF-1α axis as an important pathway in regulating glycolysis and hypoxic adaptation in tumor cells. We show that nuclear NAC1 binds to histone deacetylase type 4 (HDAC4), hindering phosphorylation of HDAC4 at Ser246 and preventing its nuclear export that leads to cytoplasmic degradation of the deacetylase. Accumulation of HDAC4 in the nuclei results in an attenuation of HIF-1α acetylation, enhancing the stabilization and transcriptional activity of HIF-1α and strengthening adaptive response of cells to hypoxia. We also show the role of NAC1 in promoting glycolysis in a mouse xenograft model, and demonstrate that knockdown of NAC1 expression can reinforce the antitumor efficacy of bevacizumab, an inhibitor of angiogenesis. Clinical implication of the NAC1-HDAC4-HIF-1α pathway is suggested by the results showing that expression levels of these proteins are significantly correlative in human tumor specimens and associated with the disease progression. This study not only reveals an important function of NAC1 in regulating glycolysis, but also identifies the NAC1-HDAC4-HIF-1α axis as a novel molecular pathway that promotes survival of hypoxic tumor cells.

Epigenetic crosstalk between hypoxia and tumor driven by HIF regulation

“…More, stable inhibition of HDAC4 in VHL-positive cells can not only reduce the transcriptional activity of HIF-1 and the expression of HIF-1 target genes, but also reduce the level of glycolysis [ 133 ]. Nucleus accumbens-associated protein-1 (NAC1), a member of the BTB/POZ gene family, can also interact with HDAC4 [ 134 ]. Intracellular accumulation of HDAC4 leads to reduced acetylation of HIF-1, but NAC1 binding to HDAC4 inhibits phosphorylation of HDAC4 at serine 246 and prevents nuclear export that leads to cytoplasmic degradation of HDAC [ 134 ].…”

“…Nucleus accumbens-associated protein-1 (NAC1), a member of the BTB/POZ gene family, can also interact with HDAC4 [ 134 ]. Intracellular accumulation of HDAC4 leads to reduced acetylation of HIF-1, but NAC1 binding to HDAC4 inhibits phosphorylation of HDAC4 at serine 246 and prevents nuclear export that leads to cytoplasmic degradation of HDAC [ 134 ]. In this context, the transcriptional activity and stability of HIF-1α was enhanced via NAC1-HDAC4-HIF-1α pathway [ 134 ].…”

“…Intracellular accumulation of HDAC4 leads to reduced acetylation of HIF-1, but NAC1 binding to HDAC4 inhibits phosphorylation of HDAC4 at serine 246 and prevents nuclear export that leads to cytoplasmic degradation of HDAC [ 134 ]. In this context, the transcriptional activity and stability of HIF-1α was enhanced via NAC1-HDAC4-HIF-1α pathway [ 134 ]. HDAC5 has been found to promote transcriptional activation of HIF-1α and nuclear accumulation of HIF-1α [ 135 ].…”

HIF-Regulated Leukemogenesis Through the Advances on Epigenetic Mechanism

“…There are evidences suggesting the targets of deacetylated p300/CBP and HIF. In this concept, HIF, P300 and HDAC4, HDAC5, or HDAC7 have been reported to form multi-polyprotein complexes [31,32]. This also shows that HDAC4 and HDAC5 could promote the binding between HIF-1 and p300, thereby enhancing the expression of HIF target genes.…”

Phosphatidylinositol 3‐Kinase–DNA Methyltransferase 1–miR‐1281–Histone Deacetylase 4 Regulatory Axis Mediates Platelet‐Derived Growth Factor–Induced Proliferation and Migration of Pulmonary Artery Smooth Muscle Cells

“…However, we found that Figure S4); therefore, we do not expect miR-1281 to exert its cellular effects by influencing the PASMC transcriptome globally. Second, because HDAC4 can act as a transcriptional coregulator that may interact with myocyte enhancer factor 2, 52 activating transcription factor 4, 53 transforming growth factor-b, 54 and hypoxia-inducible factor (HIF)-1a 55,56 in PASMCs, we investigated if miR-1281/HDAC4 pathway influenced the transcription of corresponding downstream genes kruppel-like factor 2 (KLF2), KLF4, CCAAT/enhancer-binding protein-homologous protein (CHOP), tribbles homolog 3 (TRB3), drosophila mothers against decapentaplegic protein 3 (SMAD3), vascular endothelial growth factor (VEGF), and glucose transporter-1 (GLUT-1). Our results demonstrate that inhibition of HDAC4 by siHDAC4 led to decreased mRNA levels of CHOP, SMAD3, VEGF, and GLUT-1, but increased mRNA level of TRB3 ( Figure 4A); agreeing with this, overexpression of miR-1281 by miR-1281 mimic also led to decreased mRNA levels of SMAD3, VEGF, and GLUT-1 ( Figure 4B).…”