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

Y. Zhang, Y. J. Ren, L. C. Guo, C. Ji, J. Hu, H. H. Zhang, Q. H. Xu, W. D. Zhu, Z. J. Ming, Y. S. Yuan, Xingcong Ren, J. Song, Jin-Ming Yang

Research output: Contribution to journalArticle

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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 Ser 246 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.

Original languageEnglish (US)
Pages (from-to)4171-4181
Number of pages11
JournalOncogene
Volume36
Issue number29
DOIs
StatePublished - Jul 20 2017

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Histone Deacetylases
Nucleus Accumbens
Glycolysis
Survival
Histone Deacetylase 1
Neoplasms
Proteins
NFI Transcription Factors
Cell Hypoxia
Angiogenesis Inhibitors
Cell Nucleus Active Transport
Acetylation
Heterografts
Disease Progression
Phosphorylation

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Zhang, Y., Ren, Y. J., Guo, L. C., Ji, C., Hu, J., Zhang, H. H., ... Yang, J-M. (2017). Nucleus accumbens-associated protein-1 promotes glycolysis and survival of hypoxic tumor cells via the HDAC4-HIF-1α axis. Oncogene, 36(29), 4171-4181. https://doi.org/10.1038/onc.2017.51
Zhang, Y. ; Ren, Y. J. ; Guo, L. C. ; Ji, C. ; Hu, J. ; Zhang, H. H. ; Xu, Q. H. ; Zhu, W. D. ; Ming, Z. J. ; Yuan, Y. S. ; Ren, Xingcong ; Song, J. ; Yang, Jin-Ming. / Nucleus accumbens-associated protein-1 promotes glycolysis and survival of hypoxic tumor cells via the HDAC4-HIF-1α axis. In: Oncogene. 2017 ; Vol. 36, No. 29. pp. 4171-4181.
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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 Ser 246 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.",
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Zhang, Y, Ren, YJ, Guo, LC, Ji, C, Hu, J, Zhang, HH, Xu, QH, Zhu, WD, Ming, ZJ, Yuan, YS, Ren, X, Song, J & Yang, J-M 2017, 'Nucleus accumbens-associated protein-1 promotes glycolysis and survival of hypoxic tumor cells via the HDAC4-HIF-1α axis', Oncogene, vol. 36, no. 29, pp. 4171-4181. https://doi.org/10.1038/onc.2017.51

Nucleus accumbens-associated protein-1 promotes glycolysis and survival of hypoxic tumor cells via the HDAC4-HIF-1α axis. / Zhang, Y.; Ren, Y. J.; Guo, L. C.; Ji, C.; Hu, J.; Zhang, H. H.; Xu, Q. H.; Zhu, W. D.; Ming, Z. J.; Yuan, Y. S.; Ren, Xingcong; Song, J.; Yang, Jin-Ming.

In: Oncogene, Vol. 36, No. 29, 20.07.2017, p. 4171-4181.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Nucleus accumbens-associated protein-1 promotes glycolysis and survival of hypoxic tumor cells via the HDAC4-HIF-1α axis

AU - Zhang, Y.

AU - Ren, Y. J.

AU - Guo, L. C.

AU - Ji, C.

AU - Hu, J.

AU - Zhang, H. H.

AU - Xu, Q. H.

AU - Zhu, W. D.

AU - Ming, Z. J.

AU - Yuan, Y. S.

AU - Ren, Xingcong

AU - Song, J.

AU - Yang, Jin-Ming

PY - 2017/7/20

Y1 - 2017/7/20

N2 - 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 Ser 246 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.

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