Ku70 acetylation and modulation of c-Myc/ATF4/CHOP signaling axis by SIRT1 inhibition lead to sensitization of HepG2 cells to TRAIL through induction of DR5 and down-regulation of c-FLIP

Mi-Ju Kim; Kyung-Soo Hong; Hak-Bong Kim; Su-Hoon Lee; Jae-Ho Bae; Dong-Wan Kim; Trong Tuan Dao; Won Keun Oh; Chi-Dug Kang; Sun-Hee Kim

doi:10.1016/j.biocel.2012.12.005

Ku70 acetylation and modulation of c-Myc/ATF4/CHOP signaling axis by SIRT1 inhibition lead to sensitization of HepG2 cells to TRAIL through induction of DR5 and down-regulation of c-FLIP

Mi-Ju Kim, Kyung-Soo Hong, Hak-Bong Kim, Su-Hoon Lee, Jae-Ho Bae, Dong-Wan Kim, Trong Tuan Dao, Won Keun Oh, Chi-Dug Kang, Sun-Hee Kim

13 Citations (Scopus)

Abstract

In this study, we investigated the role of c-Myc/ATF4/CHOP signaling pathway in sensitization of human hepatoma HepG2 cells to TRAIL. Knockdown of SIRT1 or treatment with SIRT1 inhibitor caused the up-regulation of DR5 and down-regulation of c-FLIP through modulation of c-Myc/ATF4/CHOP pathway, and subsequently enhanced the cytotoxic and apoptotic effects of TRAIL on HepG2 cells. Interestingly, SIRT1 interacted directly with c-FLIP(L) and Ku70, and treatment with SIRT1 inhibitor enhanced acetylation of Ku70 and subsequently decreased its binding to c-FLIP. And this was followed by degradation of c-FLIP. Moreover, Ku70(-/-) MEF and Ku70-knockdown HepG2 cells showed the increased levels of c-Myc, ATF4, CHOP, and DR5 and decreased level of c-FLIP. These results were followed by increased sensitivity of Ku70(-/-) MEF cells and Ku70-knockdown HepG2 cells to TRAIL compared with their control cells. These findings reveal for the first time that SIRT1 inhibition increases Ku70 acetylation, and the acetylated Ku70 with a decreased function mediates the induction of DR5 and the down-regulation of c-FLIP by up-regulating c-Myc/ATF4/CHOP pathway, and consequently promotes the TRAIL-induced apoptosis of HepG2 cells. This study provides important mechanistic insight of the synergism exhibited by SIRT1 inhibition and TRAIL.

Original language	English
Journal	International Journal of Biochemistry & Cell Biology
Volume	45
Issue number	3
Pages (from-to)	711-23
Number of pages	13
ISSN	1357-2725
DOIs	https://doi.org/10.1016/j.biocel.2012.12.005
Publication status	Published - Mar 2013

Keywords

Acetylation
Activating Transcription Factor 4
Animals
Antigens, Nuclear
Apoptosis
CASP8 and FADD-Like Apoptosis Regulating Protein
Cell Proliferation
DNA-Binding Proteins
Down-Regulation
Hep G2 Cells
Humans
Mice
Proto-Oncogene Proteins c-myc
Receptors, TNF-Related Apoptosis-Inducing Ligand
Signal Transduction
Sirtuin 1
TNF-Related Apoptosis-Inducing Ligand
Transcription Factor CHOP
Journal Article
Research Support, Non-U.S. Gov't

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10.1016/j.biocel.2012.12.005

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Kim, M.-J., Hong, K.-S., Kim, H.-B., Lee, S.-H., Bae, J.-H., Kim, D.-W., Dao, T. T., Oh, W. K., Kang, C.-D., & Kim, S.-H. (2013). Ku70 acetylation and modulation of c-Myc/ATF4/CHOP signaling axis by SIRT1 inhibition lead to sensitization of HepG2 cells to TRAIL through induction of DR5 and down-regulation of c-FLIP. International Journal of Biochemistry & Cell Biology, 45(3), 711-23. https://doi.org/10.1016/j.biocel.2012.12.005

Ku70 acetylation and modulation of c-Myc/ATF4/CHOP signaling axis by SIRT1 inhibition lead to sensitization of HepG2 cells to TRAIL through induction of DR5 and down-regulation of c-FLIP. / Kim, Mi-Ju; Hong, Kyung-Soo; Kim, Hak-Bong et al.
In: International Journal of Biochemistry & Cell Biology, Vol. 45, No. 3, 03.2013, p. 711-23.

Research output: Contribution to journal › Journal article › Research › peer-review

Kim, M-J, Hong, K-S, Kim, H-B, Lee, S-H, Bae, J-H, Kim, D-W, Dao, TT, Oh, WK, Kang, C-D & Kim, S-H 2013, 'Ku70 acetylation and modulation of c-Myc/ATF4/CHOP signaling axis by SIRT1 inhibition lead to sensitization of HepG2 cells to TRAIL through induction of DR5 and down-regulation of c-FLIP', International Journal of Biochemistry & Cell Biology, vol. 45, no. 3, pp. 711-23. https://doi.org/10.1016/j.biocel.2012.12.005

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title = "Ku70 acetylation and modulation of c-Myc/ATF4/CHOP signaling axis by SIRT1 inhibition lead to sensitization of HepG2 cells to TRAIL through induction of DR5 and down-regulation of c-FLIP",

abstract = "In this study, we investigated the role of c-Myc/ATF4/CHOP signaling pathway in sensitization of human hepatoma HepG2 cells to TRAIL. Knockdown of SIRT1 or treatment with SIRT1 inhibitor caused the up-regulation of DR5 and down-regulation of c-FLIP through modulation of c-Myc/ATF4/CHOP pathway, and subsequently enhanced the cytotoxic and apoptotic effects of TRAIL on HepG2 cells. Interestingly, SIRT1 interacted directly with c-FLIP(L) and Ku70, and treatment with SIRT1 inhibitor enhanced acetylation of Ku70 and subsequently decreased its binding to c-FLIP. And this was followed by degradation of c-FLIP. Moreover, Ku70(-/-) MEF and Ku70-knockdown HepG2 cells showed the increased levels of c-Myc, ATF4, CHOP, and DR5 and decreased level of c-FLIP. These results were followed by increased sensitivity of Ku70(-/-) MEF cells and Ku70-knockdown HepG2 cells to TRAIL compared with their control cells. These findings reveal for the first time that SIRT1 inhibition increases Ku70 acetylation, and the acetylated Ku70 with a decreased function mediates the induction of DR5 and the down-regulation of c-FLIP by up-regulating c-Myc/ATF4/CHOP pathway, and consequently promotes the TRAIL-induced apoptosis of HepG2 cells. This study provides important mechanistic insight of the synergism exhibited by SIRT1 inhibition and TRAIL.",

keywords = "Acetylation, Activating Transcription Factor 4, Animals, Antigens, Nuclear, Apoptosis, CASP8 and FADD-Like Apoptosis Regulating Protein, Cell Proliferation, DNA-Binding Proteins, Down-Regulation, Hep G2 Cells, Humans, Mice, Proto-Oncogene Proteins c-myc, Receptors, TNF-Related Apoptosis-Inducing Ligand, Signal Transduction, Sirtuin 1, TNF-Related Apoptosis-Inducing Ligand, Transcription Factor CHOP, Journal Article, Research Support, Non-U.S. Gov't",

author = "Mi-Ju Kim and Kyung-Soo Hong and Hak-Bong Kim and Su-Hoon Lee and Jae-Ho Bae and Dong-Wan Kim and Dao, {Trong Tuan} and Oh, {Won Keun} and Chi-Dug Kang and Sun-Hee Kim",

year = "2013",

month = mar,

doi = "10.1016/j.biocel.2012.12.005",

language = "English",

volume = "45",

pages = "711--23",

journal = "International Journal of Biochemistry & Cell Biology",

issn = "1357-2725",

publisher = "Elsevier",

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TY - JOUR

T1 - Ku70 acetylation and modulation of c-Myc/ATF4/CHOP signaling axis by SIRT1 inhibition lead to sensitization of HepG2 cells to TRAIL through induction of DR5 and down-regulation of c-FLIP

AU - Kim, Mi-Ju

AU - Hong, Kyung-Soo

AU - Kim, Hak-Bong

AU - Lee, Su-Hoon

AU - Bae, Jae-Ho

AU - Kim, Dong-Wan

AU - Dao, Trong Tuan

AU - Oh, Won Keun

AU - Kang, Chi-Dug

AU - Kim, Sun-Hee

PY - 2013/3

Y1 - 2013/3

N2 - In this study, we investigated the role of c-Myc/ATF4/CHOP signaling pathway in sensitization of human hepatoma HepG2 cells to TRAIL. Knockdown of SIRT1 or treatment with SIRT1 inhibitor caused the up-regulation of DR5 and down-regulation of c-FLIP through modulation of c-Myc/ATF4/CHOP pathway, and subsequently enhanced the cytotoxic and apoptotic effects of TRAIL on HepG2 cells. Interestingly, SIRT1 interacted directly with c-FLIP(L) and Ku70, and treatment with SIRT1 inhibitor enhanced acetylation of Ku70 and subsequently decreased its binding to c-FLIP. And this was followed by degradation of c-FLIP. Moreover, Ku70(-/-) MEF and Ku70-knockdown HepG2 cells showed the increased levels of c-Myc, ATF4, CHOP, and DR5 and decreased level of c-FLIP. These results were followed by increased sensitivity of Ku70(-/-) MEF cells and Ku70-knockdown HepG2 cells to TRAIL compared with their control cells. These findings reveal for the first time that SIRT1 inhibition increases Ku70 acetylation, and the acetylated Ku70 with a decreased function mediates the induction of DR5 and the down-regulation of c-FLIP by up-regulating c-Myc/ATF4/CHOP pathway, and consequently promotes the TRAIL-induced apoptosis of HepG2 cells. This study provides important mechanistic insight of the synergism exhibited by SIRT1 inhibition and TRAIL.

AB - In this study, we investigated the role of c-Myc/ATF4/CHOP signaling pathway in sensitization of human hepatoma HepG2 cells to TRAIL. Knockdown of SIRT1 or treatment with SIRT1 inhibitor caused the up-regulation of DR5 and down-regulation of c-FLIP through modulation of c-Myc/ATF4/CHOP pathway, and subsequently enhanced the cytotoxic and apoptotic effects of TRAIL on HepG2 cells. Interestingly, SIRT1 interacted directly with c-FLIP(L) and Ku70, and treatment with SIRT1 inhibitor enhanced acetylation of Ku70 and subsequently decreased its binding to c-FLIP. And this was followed by degradation of c-FLIP. Moreover, Ku70(-/-) MEF and Ku70-knockdown HepG2 cells showed the increased levels of c-Myc, ATF4, CHOP, and DR5 and decreased level of c-FLIP. These results were followed by increased sensitivity of Ku70(-/-) MEF cells and Ku70-knockdown HepG2 cells to TRAIL compared with their control cells. These findings reveal for the first time that SIRT1 inhibition increases Ku70 acetylation, and the acetylated Ku70 with a decreased function mediates the induction of DR5 and the down-regulation of c-FLIP by up-regulating c-Myc/ATF4/CHOP pathway, and consequently promotes the TRAIL-induced apoptosis of HepG2 cells. This study provides important mechanistic insight of the synergism exhibited by SIRT1 inhibition and TRAIL.

KW - Acetylation

KW - Activating Transcription Factor 4

KW - Animals

KW - Antigens, Nuclear

KW - Apoptosis

KW - CASP8 and FADD-Like Apoptosis Regulating Protein

KW - Cell Proliferation

KW - DNA-Binding Proteins

KW - Down-Regulation

KW - Hep G2 Cells

KW - Humans

KW - Mice

KW - Proto-Oncogene Proteins c-myc

KW - Receptors, TNF-Related Apoptosis-Inducing Ligand

KW - Signal Transduction

KW - Sirtuin 1

KW - TNF-Related Apoptosis-Inducing Ligand

KW - Transcription Factor CHOP

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1016/j.biocel.2012.12.005

DO - 10.1016/j.biocel.2012.12.005

M3 - Journal article

C2 - 23247197

SN - 1357-2725

VL - 45

SP - 711

EP - 723

JO - International Journal of Biochemistry & Cell Biology

JF - International Journal of Biochemistry & Cell Biology

IS - 3

ER -

Ku70 acetylation and modulation of c-Myc/ATF4/CHOP signaling axis by SIRT1 inhibition lead to sensitization of HepG2 cells to TRAIL through induction of DR5 and down-regulation of c-FLIP

Abstract

Keywords

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