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.
Keywords:
Dlx-2; GLS1; Snail; epithelial-mesenchymal transition; glycolytic switch.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Adenosine Triphosphate / metabolism
-
Apoptosis
-
Blotting, Western
-
Cell Proliferation
-
Chromatin Immunoprecipitation
-
Epithelial-Mesenchymal Transition*
-
Fluorescent Antibody Technique
-
Glutaminase / antagonists & inhibitors
-
Glutaminase / genetics
-
Glutaminase / metabolism*
-
Glutamine / metabolism*
-
Glycolysis / physiology*
-
HeLa Cells
-
Hep G2 Cells
-
Homeodomain Proteins / antagonists & inhibitors
-
Homeodomain Proteins / genetics
-
Homeodomain Proteins / metabolism*
-
Humans
-
MCF-7 Cells
-
Neoplasms / genetics
-
Neoplasms / metabolism
-
Neoplasms / pathology*
-
RNA, Messenger / genetics
-
Real-Time Polymerase Chain Reaction
-
Reverse Transcriptase Polymerase Chain Reaction
-
Signal Transduction
-
Snail Family Transcription Factors / antagonists & inhibitors
-
Snail Family Transcription Factors / genetics
-
Snail Family Transcription Factors / metabolism
-
Transcription Factors / antagonists & inhibitors
-
Transcription Factors / genetics
-
Transcription Factors / metabolism*
-
Transforming Growth Factor beta / antagonists & inhibitors
-
Transforming Growth Factor beta / genetics
-
Transforming Growth Factor beta / metabolism
-
Tumor Cells, Cultured
Substances
-
Distal-less homeobox proteins
-
Homeodomain Proteins
-
RNA, Messenger
-
Snail Family Transcription Factors
-
Transcription Factors
-
Transforming Growth Factor beta
-
Glutamine
-
Adenosine Triphosphate
-
GLS protein, human
-
Glutaminase