Nucleus accumbens-associated protein-1 promotes glycolysis and survival of hypoxic tumor cells via the HDAC4-HIF-1α axis.
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 Ser246and 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.
Department of Pharmacology, College of Pharmaceutical Sciences, First Affiliated Hospital, Soochow University, Jiangsu, China.
Y
Y
Zhang
Department of Pharmacology, College of Pharmaceutical Sciences, First Affiliated Hospital, Soochow University, Jiangsu, China.
Y-J
YJ
Ren
Department of Pharmacology, College of Pharmaceutical Sciences, First Affiliated Hospital, Soochow University, Jiangsu, China.
L-C
LC
Guo
Department of Pharmacology, College of Pharmaceutical Sciences, First Affiliated Hospital, Soochow University, Jiangsu, China.
C
C
Ji
Department of Pharmacology, College of Pharmaceutical Sciences, First Affiliated Hospital, Soochow University, Jiangsu, China.
J
J
Hu
Department of Pharmacology, College of Pharmaceutical Sciences, First Affiliated Hospital, Soochow University, Jiangsu, China.
H-H
HH
Zhang
Department of Pharmacology, College of Pharmaceutical Sciences, First Affiliated Hospital, Soochow University, Jiangsu, China.
Q-H
QH
Xu
Department of Pharmacology, College of Pharmaceutical Sciences, First Affiliated Hospital, Soochow University, Jiangsu, China.
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WD
Zhu
Department of Pharmacology, College of Pharmaceutical Sciences, First Affiliated Hospital, Soochow University, Jiangsu, China.
Z-J
ZJ
Ming
Engineering Research Center of Cell and Therapeutic Antibody, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China.
Y-S
YS
Yuan
Department of Pharmacology and Microbiology and Immunology, The Penn State Hershey Cancer Institute, The Pennsylvania State University College of Medicine, Hershey, PA, USA.
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X
Ren
Department of Pharmacology and Microbiology and Immunology, The Penn State Hershey Cancer Institute, The Pennsylvania State University College of Medicine, Hershey, PA, USA.
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0000-0002-9734-6176
J
Song
Department of Pharmacology and Microbiology and Immunology, The Penn State Hershey Cancer Institute, The Pennsylvania State University College of Medicine, Hershey, PA, USA.
J-M
JM
Yang
D000818:Animals; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival; D018450:Disease Progression; D005260:Female; D006019:Glycolysis; D006367:HeLa Cells; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009714:Nucleus Accumbens / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D059016:Tumor Microenvironment; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012097:Repressor Proteins; C400300:HDAC4 protein, human; D006655:Histone Deacetylases