HDAC2 provides a critical support to malignant progression of hepatocellular carcinoma through feedback control of mTORC1 and AKT.
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-κBp50 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-κBp50, 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-κBp50 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. ©2014 AACR.
Authors' Affiliations: Departments of Pathology and Biochemistry, College of Medicine; Functional RNomics Research Center; Cancer Evolution Research Center, The Catholic University of Korea; and Department of Pathology, College of Medicine, Seoul National University, Seoul, Republic of Korea.
Ji Heon
JH
Noh
Hyun Jin
HJ
Bae
Jung Woo
JW
Eun
Qingyu
Q
Shen
Se Jin
SJ
Park
Hyung Seok
HS
Kim
Boas
B
Nam
Woo Chan
WC
Shin
Eun Kyung
EK
Lee
Kyungbun
K
Lee
Ja-Jun
JJ
Jang
Won Sang
WS
Park
Jung Young
JY
Lee
Suk Woo
SW
Nam
D000818:Animals; D001483:Base Sequence; D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000401:mortality / Q000473:pathology; D018450:Disease Progression; D004815:Epidermal Growth Factor / Q000502:physiology; D066246:ErbB Receptors / Q000378:metabolism; D025461:Feedback, Physiological; D056945:Hep G2 Cells; D056464:Histone Deacetylase 2 / Q000502:physiology*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000201:enzymology* / Q000401:mortality / Q000473:pathology; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D011401:Promoter Regions, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D059467:Transcriptome
D046912:Multiprotein Complexes; D052002:NF-kappa B p50 Subunit; D004815:Epidermal Growth Factor; C512478:EGFR protein, human; D066246:ErbB Receptors; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C533423:HDAC2 protein, human; D056464:Histone Deacetylase 2