Stimulation of Fas/FasL-mediated apoptosis by luteolin through enhancement of histone H3 acetylation and c-Jun activation in HL-60 leukemia cells

Shih Wei Wang, Yun Ru Chen, Jyh Ming Chow, Ming Hsien Chien, Shun Fa Yang, Yu Ching Wen, Wei Jiunn Lee, Tsui Hwa Tseng

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2 Citations (Scopus)

Abstract

Luteolin (3',4',5,7-tetrahydroxyflavone), which exists in fruits, vegetables, and medicinal herbs, is used in Chinese traditional medicine for treating various diseases, such as hypertension, inflammatory disorders, and cancer. However, the gene-regulatory role of luteolin in cancer prevention and therapy has not been clarified. Herein, we demonstrated that treatment with luteolin resulted in a significant decrease in the viability of human leukemia cells. In the present study, by evaluating fragmentation of DNA and poly (ADP-ribose) polymerase (PARP), we found that luteolin was able to induce PARP cleavage and nuclear fragmentation as well as an increase in the sub-G0/G1 fraction. In addition, luteolin also induced Fas and Fas ligand (FasL) expressions and subsequent activation of caspases-8 and -3, which can trigger the extrinsic apoptosis pathway, while knocking down Fas-associated protein with death domain (FADD) prevented luteolin-induced PARP cleavage. Immunoblot and chromatin immunoprecipitation (ChIP) analyses revealed that luteolin increased acetylation of histone H3, which is involved in the upregulation of Fas and FasL. Moreover, both the extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) pathways are involved in luteolin-induced histone H3 acetylation. Finally, luteolin also activated the c-Jun signaling pathway, which contributes to FasL, but not Fas, gene expression and downregulation of c-Jun expression by small interfering RNA transfection which resulted in a significant decrease in luteolin-induced PARP cleavage. Thus, our results demonstrate that luteolin induced apoptosis of HL-60 cells, and this was associated with c-Jun activation and histone H3 acetylation-mediated Fas/FasL expressions.

Original languageEnglish
JournalMolecular Carcinogenesis
DOIs
Publication statusAccepted/In press - Jan 1 2018

Fingerprint

Luteolin
Fas Ligand Protein
HL-60 Cells
Acetylation
Histones
Leukemia
Apoptosis
Poly(ADP-ribose) Polymerases
Fas-Associated Death Domain Protein
Caspase 8
JNK Mitogen-Activated Protein Kinases
Chromatin Immunoprecipitation
Extracellular Signal-Regulated MAP Kinases
Chinese Traditional Medicine
DNA Fragmentation
Regulator Genes
Medicinal Plants
Caspase 3
Vegetables
Small Interfering RNA

Keywords

  • Apoptosis
  • C-Jun
  • Fas
  • Fas ligand
  • Histone acetylation
  • Luteolin

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

Cite this

@article{3ad9ef2569b44b479dbdd9c2d648bded,
title = "Stimulation of Fas/FasL-mediated apoptosis by luteolin through enhancement of histone H3 acetylation and c-Jun activation in HL-60 leukemia cells",
abstract = "Luteolin (3',4',5,7-tetrahydroxyflavone), which exists in fruits, vegetables, and medicinal herbs, is used in Chinese traditional medicine for treating various diseases, such as hypertension, inflammatory disorders, and cancer. However, the gene-regulatory role of luteolin in cancer prevention and therapy has not been clarified. Herein, we demonstrated that treatment with luteolin resulted in a significant decrease in the viability of human leukemia cells. In the present study, by evaluating fragmentation of DNA and poly (ADP-ribose) polymerase (PARP), we found that luteolin was able to induce PARP cleavage and nuclear fragmentation as well as an increase in the sub-G0/G1 fraction. In addition, luteolin also induced Fas and Fas ligand (FasL) expressions and subsequent activation of caspases-8 and -3, which can trigger the extrinsic apoptosis pathway, while knocking down Fas-associated protein with death domain (FADD) prevented luteolin-induced PARP cleavage. Immunoblot and chromatin immunoprecipitation (ChIP) analyses revealed that luteolin increased acetylation of histone H3, which is involved in the upregulation of Fas and FasL. Moreover, both the extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) pathways are involved in luteolin-induced histone H3 acetylation. Finally, luteolin also activated the c-Jun signaling pathway, which contributes to FasL, but not Fas, gene expression and downregulation of c-Jun expression by small interfering RNA transfection which resulted in a significant decrease in luteolin-induced PARP cleavage. Thus, our results demonstrate that luteolin induced apoptosis of HL-60 cells, and this was associated with c-Jun activation and histone H3 acetylation-mediated Fas/FasL expressions.",
keywords = "Apoptosis, C-Jun, Fas, Fas ligand, Histone acetylation, Luteolin",
author = "Wang, {Shih Wei} and Chen, {Yun Ru} and Chow, {Jyh Ming} and Chien, {Ming Hsien} and Yang, {Shun Fa} and Wen, {Yu Ching} and Lee, {Wei Jiunn} and Tseng, {Tsui Hwa}",
year = "2018",
month = "1",
day = "1",
doi = "10.1002/mc.22807",
language = "English",
journal = "Molecular Carcinogenesis",
issn = "0899-1987",
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TY - JOUR

T1 - Stimulation of Fas/FasL-mediated apoptosis by luteolin through enhancement of histone H3 acetylation and c-Jun activation in HL-60 leukemia cells

AU - Wang, Shih Wei

AU - Chen, Yun Ru

AU - Chow, Jyh Ming

AU - Chien, Ming Hsien

AU - Yang, Shun Fa

AU - Wen, Yu Ching

AU - Lee, Wei Jiunn

AU - Tseng, Tsui Hwa

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Luteolin (3',4',5,7-tetrahydroxyflavone), which exists in fruits, vegetables, and medicinal herbs, is used in Chinese traditional medicine for treating various diseases, such as hypertension, inflammatory disorders, and cancer. However, the gene-regulatory role of luteolin in cancer prevention and therapy has not been clarified. Herein, we demonstrated that treatment with luteolin resulted in a significant decrease in the viability of human leukemia cells. In the present study, by evaluating fragmentation of DNA and poly (ADP-ribose) polymerase (PARP), we found that luteolin was able to induce PARP cleavage and nuclear fragmentation as well as an increase in the sub-G0/G1 fraction. In addition, luteolin also induced Fas and Fas ligand (FasL) expressions and subsequent activation of caspases-8 and -3, which can trigger the extrinsic apoptosis pathway, while knocking down Fas-associated protein with death domain (FADD) prevented luteolin-induced PARP cleavage. Immunoblot and chromatin immunoprecipitation (ChIP) analyses revealed that luteolin increased acetylation of histone H3, which is involved in the upregulation of Fas and FasL. Moreover, both the extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) pathways are involved in luteolin-induced histone H3 acetylation. Finally, luteolin also activated the c-Jun signaling pathway, which contributes to FasL, but not Fas, gene expression and downregulation of c-Jun expression by small interfering RNA transfection which resulted in a significant decrease in luteolin-induced PARP cleavage. Thus, our results demonstrate that luteolin induced apoptosis of HL-60 cells, and this was associated with c-Jun activation and histone H3 acetylation-mediated Fas/FasL expressions.

AB - Luteolin (3',4',5,7-tetrahydroxyflavone), which exists in fruits, vegetables, and medicinal herbs, is used in Chinese traditional medicine for treating various diseases, such as hypertension, inflammatory disorders, and cancer. However, the gene-regulatory role of luteolin in cancer prevention and therapy has not been clarified. Herein, we demonstrated that treatment with luteolin resulted in a significant decrease in the viability of human leukemia cells. In the present study, by evaluating fragmentation of DNA and poly (ADP-ribose) polymerase (PARP), we found that luteolin was able to induce PARP cleavage and nuclear fragmentation as well as an increase in the sub-G0/G1 fraction. In addition, luteolin also induced Fas and Fas ligand (FasL) expressions and subsequent activation of caspases-8 and -3, which can trigger the extrinsic apoptosis pathway, while knocking down Fas-associated protein with death domain (FADD) prevented luteolin-induced PARP cleavage. Immunoblot and chromatin immunoprecipitation (ChIP) analyses revealed that luteolin increased acetylation of histone H3, which is involved in the upregulation of Fas and FasL. Moreover, both the extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) pathways are involved in luteolin-induced histone H3 acetylation. Finally, luteolin also activated the c-Jun signaling pathway, which contributes to FasL, but not Fas, gene expression and downregulation of c-Jun expression by small interfering RNA transfection which resulted in a significant decrease in luteolin-induced PARP cleavage. Thus, our results demonstrate that luteolin induced apoptosis of HL-60 cells, and this was associated with c-Jun activation and histone H3 acetylation-mediated Fas/FasL expressions.

KW - Apoptosis

KW - C-Jun

KW - Fas

KW - Fas ligand

KW - Histone acetylation

KW - Luteolin

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U2 - 10.1002/mc.22807

DO - 10.1002/mc.22807

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JO - Molecular Carcinogenesis

JF - Molecular Carcinogenesis

SN - 0899-1987

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