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Targeting ODC1 inhibits tumor growth through reduction of lipid metabolism in human hepatocellular carcinoma

Authors
 Yunseon Choi  ;  Sang Taek Oh  ;  Min-Ah Won  ;  Kyung Mi Choi  ;  Min Ji Ko  ;  Daekwan Seo  ;  Tae-Won Jeon  ;  In Hye Baik  ;  Sang-Kyu Ye  ;  Keon Uk Park  ;  In-Chul Park  ;  Byeong-Churl Jang  ;  Jun-Young Seo  ;  Yun-Han Lee 
Citation
 BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, Vol.478(4) : 1674-1681, 2016 
Journal Title
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
ISSN
 0006-291X 
Issue Date
2016
MeSH
Animals ; Apoptosis/genetics ; Blotting, Western ; Carcinoma, Hepatocellular/enzymology ; Carcinoma, Hepatocellular/genetics* ; Carcinoma, Hepatocellular/pathology ; Caspase 9/genetics ; Caspase 9/metabolism ; Cell Cycle/genetics ; Cell Line, Tumor ; Cell Proliferation/genetics* ; Cyclin E/genetics ; Cyclin E/metabolism ; Gene Expression Regulation, Neoplastic ; Gene Regulatory Networks ; Humans ; Kruppel-Like Transcription Factors/genetics ; Kruppel-Like Transcription Factors/metabolism ; Lipid Metabolism/genetics* ; Liver Neoplasms/enzymology ; Liver Neoplasms/genetics* ; Liver Neoplasms/pathology ; Male ; Mice, Inbred BALB C ; Mice, Nude ; Oncogene Proteins/genetics ; Oncogene Proteins/metabolism ; Ornithine Decarboxylase/genetics* ; Ornithine Decarboxylase/metabolism ; PPAR gamma/genetics ; PPAR gamma/metabolism ; Poly (ADP-Ribose) Polymerase-1/genetics ; Poly (ADP-Ribose) Polymerase-1/metabolism ; RNA Interference* ; RNAi Therapeutics/methods ; Reverse Transcriptase Polymerase Chain Reaction ; Xenograft Model Antitumor Assays/methods
Keywords
HCC ; KLF2 ; Lipogenesis ; ODC1 ; PPARγ ; Polyamine
Abstract
Ornithine decarboxylase 1 (ODC1), a metabolic enzyme critically involved in the polyamine biosynthesis, is commonly upregulated in hepatocellular carcinoma (HCC). Despite its altered expression in human HCC tissues, the molecular mechanism by which ODC1 alters the course of HCC progression and functions in HCC cell survival is unknown. Here we identified that silencing of ODC1 expression with small interfering (si) RNA causes inhibition of HCC cell growth through blockade of cell cycle progression and induction of apoptosis. Next, to obtain insights into the molecular changes in response to ODC1 knockdown, global changes in gene expression were examined using RNA sequencing. It revealed that 119 genes show same directional regulation (76 up- and 43 down-regulated) in both Huh1 and Huh7 cells and were considered as a common ODC1 knockdown signature. Particularly, we found through a network analysis that KLF2, which is known to inhibit PPARγ expression and adipogenesis, was commonly up-regulated. Subsequent Western blotting affirmed that the downregulation of ODC1 was accompanied by a decrease in the levels of PPARγ as well as of PARP-1, cyclin E1 and pro-caspase 9 delaying cell cycle progression and accelerating apoptotic signaling. Following the down-regulation of PPARγ expression, ODC1 silencing resulted in a strong inhibition in the expression of important regulators of glucose transport and lipid biogenesis, and caused a marked decrease in lipid droplet accumulation. In addition, ODC1 silencing significantly inhibited the growth of human HCC xenografts in nude mice. These findings indicate that the function of ODC1 is correlated with HCC lipogenesis and suggest that targeting ODC1 could be an attractive option for molecular therapy of HCC.
Full Text
http://www.sciencedirect.com/science/article/pii/S0006291X16314449
DOI
10.1016/j.bbrc.2016.09.002
Appears in Collections:
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
Yonsei Authors
Seo, Jun Young(서준영) ORCID logo https://orcid.org/0000-0003-4004-2013
Choi, Kyung Mi(최경미)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/152142
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