RGD Reference Report - HDAC2 provides a critical support to malignant progression of hepatocellular carcinoma through feedback control of mTORC1 and AKT. - Rat Genome Database

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HDAC2 provides a critical support to malignant progression of hepatocellular carcinoma through feedback control of mTORC1 and AKT.

Authors: Noh, JH  Bae, HJ  Eun, JW  Shen, Q  Park, SJ  Kim, HS  Nam, B  Shin, WC  Lee, EK  Lee, K  Jang, JJ  Park, WS  Lee, JY  Nam, SW 
Citation: Noh JH, etal., Cancer Res. 2014 Mar 15;74(6):1728-38. doi: 10.1158/0008-5472.CAN-13-2109. Epub 2014 Jan 21.
RGD ID: 9590206
Pubmed: PMID:24448241   (View Abstract at PubMed)
DOI: DOI:10.1158/0008-5472.CAN-13-2109   (Journal Full-text)

Aberrant regulation of histone deacetylase 2 (HDAC2) contributes to malignant progression in various cancers, but the underlying mechanism leading to the activation of oncogenic HDAC2 remains unknown. In this study, we show that HDAC2 expression is upregulated in a large cohort of patients with human hepatocellular carcinoma, and that high expression of HDAC2 was significantly associated with poor prognosis of patients with hepatocellular carcinoma. We found that mTORC1/NF-kappaBp50 signaling is necessary for the growth factor-induced HDAC2 and is sustained in hepatocellular carcinoma, but not in normal hepatic cells. Growth factor-induced mTORC1 activates the nuclear translocation of NF-kappaBp50, where it binds to the intragenic sequences of the HDAC2 gene and promotes its transcription. Hepatocellular carcinoma tissues derived from chemical-induced mouse and rat liver cancer models validated that mTORC1 activation and NF-kappaBp50 nuclear translocation are essential for the transcriptional activation of oncogenic HDAC2 in hepatocellular carcinoma. In addition, we demonstrate that HDAC2 is required to maintain mTORC1 activity by stabilizing the mTOR/RAPTOR complex. Elevated expression of HDAC2 triggers a positive feedback loop that activates AKT phosphorylation via the transcriptional modulation of phosphoinositide signaling molecules. Bioinformatics analysis of HDAC2 signature and immunoblot analysis of mesenchymal genes also evidenced that HDAC2 plays a role in the malignant behavior of tumor cells by Snail induction and simultaneously E-cadherin suppression in hepatocellular carcinoma cells. These findings establish a molecular mechanism responsible for the activation of oncogenic HDAC2, which explains how growth factor-induced HDAC2 maintains mitogenic signaling and function during hepatocellular malignant progression and provide a novel strategy for therapeutic intervention in liver cancer. Cancer Res; 74(6); 1728-38. (c)2014 AACR.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
HDAC2Humanhepatocellular carcinoma disease_progressionIEP mRNA:increased expression:liver:RGD 
Hdac2Rathepatocellular carcinoma disease_progressionISOHDAC2 (Homo sapiens)mRNA:increased expression:liver:RGD 
Hdac2Mousehepatocellular carcinoma disease_progressionISOHDAC2 (Homo sapiens)mRNA:increased expression:liver:RGD 

Objects Annotated

Genes (Rattus norvegicus)
Hdac2  (histone deacetylase 2)

Genes (Mus musculus)
Hdac2  (histone deacetylase 2)

Genes (Homo sapiens)
HDAC2  (histone deacetylase 2)


Additional Information