title: A pivotal role of Krüppel-like factor 5 in regulation of cancer stem-like cells in hepatocellular carcinoma.
abstract: In hepatocellular carcinoma (HCC), there exists a highly tumorigenic subset of cells defined by high expression of CD44 and CD133 that has been reported to contain cancer stem-like cells (CSCs). Krüppel-like factor 5 (KLF5) regulates many factors involved in cell cycle, migration, inflammation, angiogenesis and stemness and has cancer-promoting effects in some cancers. While some reports have indicated that KLF5 may have important roles in regulation of CSCs, what role, if any, KLF5 plays in regulation of CSCs in HCC remains to be elucidated. Flow cytometric analysis of CD44 and CD133 in HCC cell lines revealed subpopulations of CD44(High)/CD133(High) and CD44(Low)/CD133(Low) cells. We subsequently sorted these subpopulations and identified KLF5 as a gene that is significantly upregulated in CD44(High)/CD44(High) cells via RNA sequencing using next generation sequencing technology. Moreover, KLF5 overexpression enriched the CD44(High)/CD133(High) subpopulation and, consistent with the up-regulation of CD44(High)/CD133(High) cells, KLF5 overexpressing cells were more resistant to anti-cancer drugs and displayed enhanced colony-formation capacity. By contrast, knock-down of KLF5 by siRNA diminished the CD44(High)/CD133(High) subpopulation. When KLF5 was acetylated by TGF-β1, the KLF5-mediated CD44(High)/CD133(High) subpopulation enrichment was abrogated. Oppositely, ectopic expression of an acetylation-deficient KLF5 mutant further increased CD44(High)/CD133(High) subpopulations as compared to cell expressing wild-type KLF5. These findings provide novel mechanistic insight into a pivotal role for KLF5 in the regulation of CSCs in HCC.
authors.affiliation: a Department of Gastroenterology and Hepatology ; Hokkaido University Graduate School of Medicine ; Sapporo , Japan.|b Pathophysiology and Therapeutics ; Hokkaido University Graduate School of Pharmaceutical Science ; Sapporo , Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Maehara
authors.affiliation: a Department of Gastroenterology and Hepatology ; Hokkaido University Graduate School of Medicine ; Sapporo , Japan.
authors.forename: Fumiyuki
authors.initials: F
authors.lastname: Sato
authors.affiliation: a Department of Gastroenterology and Hepatology ; Hokkaido University Graduate School of Medicine ; Sapporo , Japan.
authors.forename: Mitsuteru
authors.initials: M
authors.lastname: Natsuizaka
authors.affiliation: a Department of Gastroenterology and Hepatology ; Hokkaido University Graduate School of Medicine ; Sapporo , Japan.|b Pathophysiology and Therapeutics ; Hokkaido University Graduate School of Pharmaceutical Science ; Sapporo , Japan.
authors.forename: Ayaka
authors.initials: A
authors.lastname: Asano
authors.affiliation: a Department of Gastroenterology and Hepatology ; Hokkaido University Graduate School of Medicine ; Sapporo , Japan.
authors.forename: Yoshimasa
authors.initials: Y
authors.lastname: Kubota
authors.affiliation: a Department of Gastroenterology and Hepatology ; Hokkaido University Graduate School of Medicine ; Sapporo , Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Itoh
authors.affiliation: a Department of Gastroenterology and Hepatology ; Hokkaido University Graduate School of Medicine ; Sapporo , Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Tsunematsu
authors.affiliation: a Department of Gastroenterology and Hepatology ; Hokkaido University Graduate School of Medicine ; Sapporo , Japan.
authors.forename: Katsumi
authors.initials: K
authors.lastname: Terashita
authors.affiliation: a Department of Gastroenterology and Hepatology ; Hokkaido University Graduate School of Medicine ; Sapporo , Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Tsukuda
authors.affiliation: a Department of Gastroenterology and Hepatology ; Hokkaido University Graduate School of Medicine ; Sapporo , Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Nakai
authors.affiliation: a Department of Gastroenterology and Hepatology ; Hokkaido University Graduate School of Medicine ; Sapporo , Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Sho
authors.affiliation: a Department of Gastroenterology and Hepatology ; Hokkaido University Graduate School of Medicine ; Sapporo , Japan.
authors.forename: Goki
authors.initials: G
authors.lastname: Suda
authors.affiliation: a Department of Gastroenterology and Hepatology ; Hokkaido University Graduate School of Medicine ; Sapporo , Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Morikawa
authors.affiliation: a Department of Gastroenterology and Hepatology ; Hokkaido University Graduate School of Medicine ; Sapporo , Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Ogawa
authors.affiliation: c Gastroenterological Center ; Yokohama City University Medical Center ; Yokohama , Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Chuma
authors.affiliation: b Pathophysiology and Therapeutics ; Hokkaido University Graduate School of Pharmaceutical Science ; Sapporo , Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Nakagawa
authors.affiliation: a Department of Gastroenterology and Hepatology ; Hokkaido University Graduate School of Medicine ; Sapporo , Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Ohnishi
authors.affiliation: a Department of Gastroenterology and Hepatology ; Hokkaido University Graduate School of Medicine ; Sapporo , Japan.
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Komatsu
authors.affiliation: d Gastroenterology Division ; University of Pennsylvania ; Philadelphia , PA USA.|e Abramson Cancer Center ; Philadelphia , PA USA.
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Whelan
authors.affiliation: d Gastroenterology Division ; University of Pennsylvania ; Philadelphia , PA USA.|e Abramson Cancer Center ; Philadelphia , PA USA.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nakagawa
authors.affiliation: b Pathophysiology and Therapeutics ; Hokkaido University Graduate School of Pharmaceutical Science ; Sapporo , Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takeda
authors.affiliation: a Department of Gastroenterology and Hepatology ; Hokkaido University Graduate School of Medicine ; Sapporo , Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Sakamoto
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000473:pathology
chemical_list: D051741:Kruppel-Like Transcription Factors
keywords: CD133; CD44; KLF5; acetylation; cancer stem cell; hepatocellular carcinoma