title: Dlx-2 and glutaminase upregulate epithelial-mesenchymal transition and glycolytic switch.
abstract: Most cancer cells depend on enhanced glucose and glutamine (Gln) metabolism for growth and survival. Oncogenic metabolism provides biosynthetic precursors for nucleotides, lipids, and amino acids; however, its specific roles in tumor progression are largely unknown. We previously showed that distal-less homeobox-2 (Dlx-2), a homeodomain transcription factor involved in embryonic and tumor development, induces glycolytic switch and epithelial-mesenchymal transition (EMT) by inducing Snail expression. Here we show that Dlx-2 also induces the expression of the crucial Gln metabolism enzyme glutaminase (GLS1), which converts Gln to glutamate. TGF-β and Wnt induced GLS1 expression in a Dlx-2-dependent manner. GLS1 shRNA (shGLS1) suppressed in vivo tumor metastasis and growth. Inhibition of Gln metabolism by shGLS1, Gln deprivation, and Gln metabolism inhibitors (DON, 968 and BPTES) prevented Dlx-2-, TGF-β-, Wnt-, and Snail-induced EMT and glycolytic switch. Finally, shDlx-2 and Gln metabolism inhibition decreased Snail mRNA levels through p53-dependent upregulation of Snail-targeting microRNAs. These results demonstrate that the Dlx-2/GLS1/Gln metabolism axis is an important regulator of TGF-β/Wnt-induced, Snail-dependent EMT, metastasis, and glycolytic switch.
authors.affiliation: Department of Molecular Biology, College of Natural Sciences, Pusan 609-735, Korea.
authors.forename: Su Yeon
authors.initials: SY
authors.lastname: Lee
authors.affiliation: Department of Molecular Biology, College of Natural Sciences, Pusan 609-735, Korea.
authors.forename: Hyun Min
authors.initials: HM
authors.lastname: Jeon
authors.affiliation: Department of Molecular Biology, College of Natural Sciences, Pusan 609-735, Korea.
authors.forename: Min Kyung
authors.initials: MK
authors.lastname: Ju
authors.affiliation: Department of Molecular Biology, College of Natural Sciences, Pusan 609-735, Korea.
authors.forename: Eui Kyong
authors.initials: EK
authors.lastname: Jeong
authors.affiliation: Department of Molecular Biology, College of Natural Sciences, Pusan 609-735, Korea.
authors.forename: Cho Hee
authors.initials: CH
authors.lastname: Kim
authors.affiliation: Nanobiotechnology Center, Pusan National University, Pusan 609-735, Korea.
authors.forename: Hye Gyeong
authors.initials: HG
authors.lastname: Park
authors.affiliation: The Division of Natural Medical Sciences, College of Health Science, Chosun University, Gwangju 501-759, Korea.
authors.forename: Song Iy
authors.initials: SI
authors.lastname: Han
authors.affiliation: Department of Molecular Biology, College of Natural Sciences, Pusan 609-735, Korea.
authors.forename: Ho Sung
authors.initials: HS
authors.lastname: Kang
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D017209:Apoptosis; D015153:Blotting, Western; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D058750:Epithelial-Mesenchymal Transition; D005455:Fluorescent Antibody Technique; D005972:Glutaminase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005973:Glutamine / Q000378:metabolism*; D006019:Glycolysis / Q000502:physiology*; D006367:HeLa Cells; D056945:Hep G2 Cells; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D061986:MCF-7 Cells; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: C088334:Distal-less homeobox proteins; D018398:Homeodomain Proteins; D012333:RNA, Messenger; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D005973:Glutamine; D000255:Adenosine Triphosphate; C579480:GLS protein, human; D005972:Glutaminase
keywords: Dlx-2; GLS1; Snail; epithelial-mesenchymal transition; glycolytic switch