Oncogenic role of PDK4 in human colon cancer cells

被引:90
作者
Leclerc, D. [1 ]
Pham, D. N. T. [1 ]
Levesque, N. [1 ]
Truongcao, M. [2 ]
Foulkes, W. D. [3 ,4 ,5 ]
Sapienza, C. [2 ]
Rozen, R. [1 ]
机构
[1] McGill Univ, McGill Univ Hlth Ctr, Res Inst, Dept Human Genet & Pediat, 1001 Decarie Blvd,Room E M0 3211, Montreal, PQ H4A 3J1, Canada
[2] Temple Univ, Sch Med, Fels Inst Canc Res & Mol Biol, Philadelphia, PA 19122 USA
[3] McGill Univ, McGill Univ Hlth Ctr, Res Inst, Dept Med Genet, Montreal, PQ, Canada
[4] Jewish Gen Hosp, Segal Canc Ctr, Lady Davis Inst, Montreal, PQ, Canada
[5] McGill Univ, Dept Oncol & Human Genet, Program Canc Genet, Montreal, PQ, Canada
基金
加拿大健康研究院;
关键词
PYRUVATE-DEHYDROGENASE COMPLEX; MURINE PRENEOPLASTIC INTESTINE; REMODELS PROMOTER METHYLATION; INDUCIBLE FACTOR 1-ALPHA; DICHLOROACETATE DCA; SKELETAL-MUSCLE; METABOLISM; HYPOXIA; TUMORIGENESIS; APOPTOSIS;
D O I
10.1038/bjc.2017.38
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Background: Cancer cells maintain high rates of glycolysis. Pyruvate dehydrogenase kinases (PDK) contribute to this phenomenon, which favours apoptosis resistance and cellular transformation. We previously reported upregulation of PDK4 in normal mucosa of colorectal cancer (CRC) patients compared with controls and in preneoplastic intestine of our mouse model. Decreased methylation of four consecutive PDK4 CpGs was observed in normal mucosa of patients. Although other members of the PDK family have been investigated for transformation potential, PDK4 has not been extensively studied. Methods: PDK4 methylation in blood of CRC patients and controls was evaluated by pyrosequencing. PDK4 expression in human colon carcinoma cells was down-regulated by RNAi. Cellular migration and invasion, apoptosis and qRT-PCR of key genes were assessed. Results: Pyrosequencing revealed decreased methylation of the same four consecutive CpGs in the blood of patients compared with controls. Cellular migration and invasion were reduced and apoptosis was increased following transient or stable inhibition of PDK4. Expression of vimentin, HIF-1 and VEGFA was reduced. Conclusions: These studies demonstrate the involvement of PDK4 in transformation. Methylation assessment of PDK4 in the blood may be useful for non-invasive CRC detection. PDK4 should be considered as a target for development of anticancer strategies and therapies
引用
收藏
页码:930 / 936
页数:7
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