Upregulation of KLF4 by methylseleninic acid in human esophageal squamous cell carcinoma cells: Modification of histone H3 acetylation through HAT/HDAC interplay.
Esophageal squamous cell carcinoma (ESCC) occurs at a very high frequency in certain areas of China. Supplementation with selenium-containing compounds was associated with a significantly lower cancer mortality rate in a study conducted in Linxia, China. Thus, selenium could be a potential anti-esophageal cancer agent. In this study, methylseleninic acid (MSA) could inhibit cell growth of ESCC cells in vitro and in vivo. Upon treated with MSA, the activity of histone deacetylases (HDACs) was decreased and general control nonrepressed protein 5 (GCN5) was upregulated in ESCC cells. Meanwhile, a significant increase of H3K9 acetylation (H3K9ac) was detected. Upregulation of Krüppel-like factor 4 (KLF4) was also observed after MSA treatment. Additionally, the acetylated histone H3 located more at KLF4 promoter region after MSA treatment, shown by chromatin immunoprecipitation (ChIP) assay. Moreover, knockdown of GCN5 decreased the protein level of both H3K9ac and KLF4, along with less cell growth inhibition. Taken all, our results indicated that MSA could inhibit ESCC cell growth, at least in part, by MSA-HDAC/GCN5-H3K9ac-KLF4 axis. To our best knowledge, this is the first report that MSA induced acetylation of histone H3 at Lys9, which might depend on the activities and the balance between HDACs and HATs.
Laboratory of Cell and Molecular Biology and State Key Laboratory of Molecular Oncology, Cancer Institute and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR, China.
Chenfei
C
Hu
Laboratory of Cell and Molecular Biology and State Key Laboratory of Molecular Oncology, Cancer Institute and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR, China.
Mei
M
Liu
Laboratory of Cell and Molecular Biology and State Key Laboratory of Molecular Oncology, Cancer Institute and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR, China.
Wei
W
Zhang
Laboratory of Cell and Molecular Biology and State Key Laboratory of Molecular Oncology, Cancer Institute and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR, China.
Qing
Q
Xu
Laboratory of Cell and Molecular Biology and State Key Laboratory of Molecular Oncology, Cancer Institute and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR, China.
Kai
K
Ma
Laboratory of Cell and Molecular Biology and State Key Laboratory of Molecular Oncology, Cancer Institute and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR, China.
Lechuang
L
Chen
Laboratory of Cell and Molecular Biology and State Key Laboratory of Molecular Oncology, Cancer Institute and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR, China.
Zaozao
Z
Wang
Laboratory of Cell and Molecular Biology and State Key Laboratory of Molecular Oncology, Cancer Institute and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR, China.
Shun
S
He
Laboratory of Cell and Molecular Biology and State Key Laboratory of Molecular Oncology, Cancer Institute and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR, China.
Hongxia
H
Zhu
Laboratory of Cell and Molecular Biology and State Key Laboratory of Molecular Oncology, Cancer Institute and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR, China.
Ningzhi
N
Xu
D000107:Acetylation / Q000187:drug effects*; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D047369:Chromatin Immunoprecipitation / Q000379:methods; D004938:Esophageal Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D000077277:Esophageal Squamous Cell Carcinoma; D051548:Histone Acetyltransferases / Q000378:metabolism*; D006655:Histone Deacetylases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016566:Organoselenium Compounds / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
D006657:Histones; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D016566:Organoselenium Compounds; C008493:methylselenic acid; D051548:Histone Acetyltransferases; D006655:Histone Deacetylases
GCN5; KLF4; histone acetylation; selenium