Targeting ODC1 inhibits tumor growth through reduction of lipid metabolism in human hepatocellular carcinoma.
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.
Department of Radiation Oncology, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; Department of Radiation Oncology, Busan Paik Hospital, Inje University School of Medicine, Busan 47392, Republic of Korea.
Yunseon
Y
Choi
Department of Radiation Oncology, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; Department of Molecular Medicine, Keimyung University School of Medicine, 1095 Dalgubeol-daero, Dalseo-gu, Daegu 42601, Republic of Korea.
Sang Taek
ST
Oh
Department of Molecular Medicine, Keimyung University School of Medicine, 1095 Dalgubeol-daero, Dalseo-gu, Daegu 42601, Republic of Korea.
Min-Ah
MA
Won
Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea.
Kyung Mi
KM
Choi
Department of Molecular Medicine, Keimyung University School of Medicine, 1095 Dalgubeol-daero, Dalseo-gu, Daegu 42601, Republic of Korea.
Min Ji
MJ
Ko
Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea.
Daekwan
D
Seo
Department of Radiation Oncology, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; Department of Molecular Medicine, Keimyung University School of Medicine, 1095 Dalgubeol-daero, Dalseo-gu, Daegu 42601, Republic of Korea.
Tae-Won
TW
Jeon
Department of Radiation Oncology, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; Department of Molecular Medicine, Keimyung University School of Medicine, 1095 Dalgubeol-daero, Dalseo-gu, Daegu 42601, Republic of Korea.
In Hye
IH
Baik
Department of Pharmacology and Biomedical Sciences, Biomedical Science Project (BK21(PLUS)), Seoul National University College of Medicine, Seoul 03080, Republic of Korea.
Sang-Kyu
SK
Ye
Department of Internal Medicine, Dongsan Medical Center, Keimyung University, Daegu 41931, Republic of Korea.
Keon Uk
KU
Park
Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences, Seoul 01812, Republic of Korea.
In-Chul
IC
Park
Department of Molecular Medicine, Keimyung University School of Medicine, 1095 Dalgubeol-daero, Dalseo-gu, Daegu 42601, Republic of Korea.
Byeong-Churl
BC
Jang
Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea. Electronic address: jyseo0724@yuhs.ac.
Jun-Young
JY
Seo
Department of Molecular Medicine, Keimyung University School of Medicine, 1095 Dalgubeol-daero, Dalseo-gu, Daegu 42601, Republic of Korea. Electronic address: yhlee87@kmu.ac.kr.
Yun-Han
YH
Lee
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D053453:Caspase 9 / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics*; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D050356:Lipid Metabolism / Q000235:genetics*; D008113:Liver Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D009955:Ornithine Decarboxylase / Q000235:genetics* / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D000067492:RNAi Therapeutics / Q000379:methods; D020133:Reverse Transcriptase Polymerase Chain Reaction; D023041:Xenograft Model Antitumor Assays / Q000379:methods
C475820:CCNE1 protein, human; D019927:Cyclin E; C096161:KLF2 protein, human; D051741:Kruppel-Like Transcription Factors; D015513:Oncogene Proteins; D047495:PPAR gamma; D000071137:Poly (ADP-Ribose) Polymerase-1; D053453:Caspase 9; D009955:Ornithine Decarboxylase
HCC; KLF2; Lipogenesis; ODC1; PPARγ; Polyamine