title: Krüppel-like factor 8 contributes to hypoxia-induced MDR in gastric cancer cells.
abstract: We previously reported that hypoxia-induced MDR in gastric cancer (GC) cells is hypoxia-inducible factor-1 (HIF-1)-dependent. However, the exact mechanisms are still unknown. Our previous study revealed that Krüppel-like factor 8 (KLF8), a novel transcription factor, was associated with malignant phenotype in GC cells. KLF8 is overexpressed in clear cell renal carcinoma lacking von Hippel-Lindau protein function, which resulted in HIF-1 stabilization. Given this association, we hypothesized that KLF8 contributed to hypoxia-induced MDR in GC cells. Initial experiments revealed that hypoxia could increase KLF8 and HIF-1α expressions in GC cells, and KLF8 levels in GC drug-resistant cell lines were higher than in parental cell lines. Subsequent experiments showed that in normoxia, exogenous KLF8 could promote the MDR phenotype; however, blocking KLF8 expression could effectively reverse the MDR phenotype induced by hypoxia. Overexpressed KLF8 increased resistance-associated gene MDR1 mRNA levels, Bcl-2 and P-gp protein levels, and decreased Bax and caspase-3 protein levels in GC cells, and knockout KLF8 reversed these effects. Dual luciferase reporter and ChIP assays showed that KLF8 could promote MDR1 transcriptional activity by combining with KLF8 binding sites located in the upstream of MDR1 transcriptional start site. These results suggest that KLF8 is involved in hypoxia-induced MDR through inhibiting apoptosis and increasing the drug release rate by directly regulating MDR1 transcription.
authors.affiliation: Department of Oncology, Tangdu Hospital, Fourth Military Medical University, Xi'an, China; Department of Tuberculosis Control and Prevention, Xi'an Center for Disease Control and Prevention, Xi'an, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.forename: Li
authors.initials: L
authors.lastname: Sun
authors.forename: Xiao
authors.initials: X
authors.lastname: Xiao
authors.forename: Rougang
authors.initials: R
authors.lastname: Xie
authors.forename: Changhao
authors.initials: C
authors.lastname: Liu
authors.forename: Yafang
authors.initials: Y
authors.lastname: Wang
authors.forename: Yanling
authors.initials: Y
authors.lastname: Wei
authors.forename: Hongbo
authors.initials: H
authors.lastname: Zhang
authors.forename: Lili
authors.initials: L
authors.lastname: Liu
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors; D012097:Repressor Proteins / Q000502:physiology*; D013274:Stomach Neoplasms; D014158:Transcription, Genetic; D015533:Transcriptional Activation
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D051017:Apoptosis Regulatory Proteins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C507402:KLF8 protein, human; D051741:Kruppel-Like Transcription Factors; D012097:Repressor Proteins; D004317:Doxorubicin
keywords: Gastric cancer cells; Krüppel-like factor 8; hypoxia; multidrug resistance; normoxia