Vitamin D3 upregulated protein 1 suppresses TNF-α-induced NF-κB activation in hepatocarcinogenesis.
Vitamin D(3) upregulated protein 1 (VDUP1) is a candidate tumor suppressor, the expression of which is dramatically reduced in various tumor tissues. In this study, we found that VDUP1 expression is suppressed during human hepatic carcinogenesis, and mice lacking VDUP1 are much more susceptible to diethylnitrosamine-induced hepatocarcinogenesis compared with wild type mice. VDUP1-deficient tumors proliferated significantly more than wild type tumors and had corresponding changes in the expression of key cell cycle regulatory proteins. In addition, the hepatomitogen-induced response was associated with a considerable increase in the release of TNF-α and subsequent enhancement of NF-κB activation in VDUP1-deficient mice. When cells were treated with TNF-α, the VDUP1 level was markedly reduced, concomitant with elevated NF-κB activation. Furthermore, the overexpression of VDUP1 resulted in the robust suppression of TNF-α-activated NF-κB activity via association with HDAC1 and HDAC3. These results indicate that VDUP1 negatively regulates hepatocarcinogenesis by suppressing TNF-α-induced NF-κB activation.
Kwon
Hyo-Jung
HJ
Bio-Evaluation Center, Korea Research Institute of Bioscience and Biotechnology, Chungbuk, South Korea.
Won
Young-Suk
YS
Suh
Hyun-Woo
HW
Jeon
Jun-Ho
JH
Shao
Yan
Y
Yoon
Suk-Ran
SR
Chung
Jin-Woong
JW
Kim
Tae-Don
TD
Kim
Hwan-Mook
HM
Nam
Ki-Hoan
KH
Yoon
Won-Kee
WK
Kim
Dae-Ghon
DG
Kim
Jeong-Hwan
JH
Kim
Young-Sung
YS
Kim
Dae-Yong
DY
Kim
Hyoung-Chin
HC
Choi
Inpyo
I
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D004789:Enzyme Activation / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D020287:In Situ Nick-End Labeling; D008113:Liver Neoplasms / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D016328:NF-kappa B / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D013879:Thioredoxins / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D002352:Carrier Proteins; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; C445672:Txnip protein, mouse; D013879:Thioredoxins