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Histone deacetylase 5 promotes the migration and invasion of hepatocellular carcinoma via increasing the transcription of hypoxia-inducible factor-1α under hypoxia condition.

Abstract Hypoxia plays a critical role in the progression and metastasis of hepatocellular carcinoma by activating the key transcription factor, hypoxia-inducible factor-1. This study aims to identify the novel mechanisms underlying the dysregulation of hypoxia-inducible factor-1α in hepatocellular carcinoma. We found that histone deacetylase 5, a highly expressed histone deacetylase in hepatocellular carcinoma, strengthened the migration and invasion of hepatocellular carcinoma cells under hypoxia but not normoxia condition. Furthermore, histone deacetylase 5 induced the transcription of hypoxia-inducible factor-1α by silencing homeodomain-interacting protein kinase-2 expression, which was also dependent on hypoxia. And then knockdown of hypoxia-inducible factor-1α decreased the expressions of mesenchymal markers, N-cadherin, and Vimentin, as well as matrix metalloproteinases, MMP7 and MMP9; however, the epithelial marker, E-cadherin, increased. Phenotype experiments showed that the migration and invasion of hepatocellular carcinoma cells were impaired by knockdown of histone deacetylase 5 or hypoxia-inducible factor-1α but rescued when eliminating homeodomain-interacting protein kinase-2 in hepatocellular carcinoma cells, which suggested the critical role of histone deacetylase 5-homeodomain-interacting protein kinase-2-hypoxia-inducible factor-1α pathway in hypoxia-induced metastasis. Finally, clinical analysis confirmed the positive correlation between histone deacetylase 5 and hypoxia-inducible factor-1α in hepatocellular carcinoma specimens and a relatively poor prognosis for the patients with high levels of histone deacetylase 5 and hypoxia-inducible factor-1α. Taken together, our findings demonstrated a novel mechanism underlying the crosstalk between histone deacetylase 5 and hypoxia-inducible factor-1 in hepatocellular carcinoma.
PMID
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Authors

Mayor MeshTerms
Keywords

Hypoxia

hepatocellular carcinoma

histone deacetylase

homeodomain-interacting protein kinase-2

hypoxia-inducible factor-1

Journal Title tumour biology : the journal of the international society for oncodevelopmental biology and medicine
Publication Year Start




PMID- 28653891
OWN - NLM
STAT- MEDLINE
DA  - 20170627
DCOM- 20170711
LR  - 20170713
IS  - 1423-0380 (Electronic)
IS  - 1010-4283 (Linking)
VI  - 39
IP  - 6
DP  - 2017 Jun
TI  - Histone deacetylase 5 promotes the migration and invasion of hepatocellular
      carcinoma via increasing the transcription of hypoxia-inducible factor-1alpha
      under hypoxia condition.
PG  - 1010428317705034
LID - 10.1177/1010428317705034 [doi]
AB  - Hypoxia plays a critical role in the progression and metastasis of hepatocellular
      carcinoma by activating the key transcription factor, hypoxia-inducible factor-1.
      This study aims to identify the novel mechanisms underlying the dysregulation of 
      hypoxia-inducible factor-1alpha in hepatocellular carcinoma. We found that
      histone deacetylase 5, a highly expressed histone deacetylase in hepatocellular
      carcinoma, strengthened the migration and invasion of hepatocellular carcinoma
      cells under hypoxia but not normoxia condition. Furthermore, histone deacetylase 
      5 induced the transcription of hypoxia-inducible factor-1alpha by silencing
      homeodomain-interacting protein kinase-2 expression, which was also dependent on 
      hypoxia. And then knockdown of hypoxia-inducible factor-1alpha decreased the
      expressions of mesenchymal markers, N-cadherin, and Vimentin, as well as matrix
      metalloproteinases, MMP7 and MMP9; however, the epithelial marker, E-cadherin,
      increased. Phenotype experiments showed that the migration and invasion of
      hepatocellular carcinoma cells were impaired by knockdown of histone deacetylase 
      5 or hypoxia-inducible factor-1alpha but rescued when eliminating
      homeodomain-interacting protein kinase-2 in hepatocellular carcinoma cells, which
      suggested the critical role of histone deacetylase 5-homeodomain-interacting
      protein kinase-2-hypoxia-inducible factor-1alpha pathway in hypoxia-induced
      metastasis. Finally, clinical analysis confirmed the positive correlation between
      histone deacetylase 5 and hypoxia-inducible factor-1alpha in hepatocellular
      carcinoma specimens and a relatively poor prognosis for the patients with high
      levels of histone deacetylase 5 and hypoxia-inducible factor-1alpha. Taken
      together, our findings demonstrated a novel mechanism underlying the crosstalk
      between histone deacetylase 5 and hypoxia-inducible factor-1 in hepatocellular
      carcinoma.
FAU - Ye, Ming
AU  - Ye M
AD  - 1 Department of General Surgery, Sanmen People's Hospital of Zhejiang, Sanmen,
      China.
FAU - Fang, Zejun
AU  - Fang Z
AD  - 2 Central Laboratory, Sanmen People's Hospital of Zhejiang, Sanmen, China.
FAU - Gu, Hongqian
AU  - Gu H
AD  - 1 Department of General Surgery, Sanmen People's Hospital of Zhejiang, Sanmen,
      China.
FAU - Song, Rui
AU  - Song R
AD  - 3 Department of Pathology, The Second Affiliated Hospital Zhejiang University
      School of Medicine, Hangzhou, China.
FAU - Ye, Jiangwei
AU  - Ye J
AD  - 1 Department of General Surgery, Sanmen People's Hospital of Zhejiang, Sanmen,
      China.
FAU - Li, Hongzhang
AU  - Li H
AD  - 4 Department of Gastroenterology, Sanmen People's Hospital of Zhejiang, Sanmen,
      China.
FAU - Wu, Zhiguang
AU  - Wu Z
AD  - 1 Department of General Surgery, Sanmen People's Hospital of Zhejiang, Sanmen,
      China.
FAU - Zhou, Shenghui
AU  - Zhou S
AD  - 1 Department of General Surgery, Sanmen People's Hospital of Zhejiang, Sanmen,
      China.
FAU - Li, Peng
AU  - Li P
AD  - 1 Department of General Surgery, Sanmen People's Hospital of Zhejiang, Sanmen,
      China.
FAU - Cai, Xiang
AU  - Cai X
AD  - 1 Department of General Surgery, Sanmen People's Hospital of Zhejiang, Sanmen,
      China.
FAU - Ding, Xiaokun
AU  - Ding X
AD  - 1 Department of General Surgery, Sanmen People's Hospital of Zhejiang, Sanmen,
      China.
FAU - Yu, Songshan
AU  - Yu S
AD  - 2 Central Laboratory, Sanmen People's Hospital of Zhejiang, Sanmen, China.
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Tumour Biol
JT  - Tumour biology : the journal of the International Society for Oncodevelopmental
      Biology and Medicine
JID - 8409922
RN  - 0 (Carrier Proteins)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Neoplasm Proteins)
RN  - EC 2.7.1.- (HIPK2 protein, human)
RN  - EC 2.7.11.1 (Protein-Serine-Threonine Kinases)
RN  - EC 3.5.1.98 (HDAC5 protein, human)
RN  - EC 3.5.1.98 (Histone Deacetylases)
SB  - IM
MH  - Aged
MH  - Carcinoma, Hepatocellular/*genetics/pathology
MH  - Carrier Proteins/antagonists & inhibitors/*genetics
MH  - Cell Hypoxia/genetics
MH  - Cell Movement/genetics
MH  - Cell Proliferation/genetics
MH  - Female
MH  - Histone Deacetylases/*genetics
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/*genetics
MH  - Liver Neoplasms/*genetics/pathology
MH  - Male
MH  - Middle Aged
MH  - Neoplasm Invasiveness/genetics
MH  - Neoplasm Proteins/biosynthesis
MH  - Protein-Serine-Threonine Kinases/antagonists & inhibitors/*genetics
OTO - NOTNLM
OT  - Hypoxia
OT  - hepatocellular carcinoma
OT  - histone deacetylase
OT  - homeodomain-interacting protein kinase-2
OT  - hypoxia-inducible factor-1
EDAT- 2017/06/28 06:00
MHDA- 2017/07/14 06:00
CRDT- 2017/06/28 06:00
AID - 10.1177/1010428317705034 [doi]
PST - ppublish
SO  - Tumour Biol. 2017 Jun;39(6):1010428317705034. doi: 10.1177/1010428317705034.