Dlx-2 and glutaminase upregulate epithelial-mesenchymal transition and glycolytic switch.

Oncotarget
Su Yeon LeeHo Sung Kang

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, metas...Continue Reading

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Citations

Apr 27, 2017·The FEBS Journal·Marco Sciacovelli, Christian Frezza
Apr 11, 2018·Oxidative Medicine and Cellular Longevity·Su Yeon LeeHo Sung Kang
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Jan 24, 2019·Oxidative Medicine and Cellular Longevity·Su Yeon LeeHo Sung Kang
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May 1, 2021·Cancers·Josep Tarragó-Celada, Marta Cascante
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Jun 6, 2021·Molecular Cancer Research : MCR·Sigurdur Trausti KarvelssonSkarphedinn Halldorsson

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Datasets Mentioned

BETA
GSE61009

Methods Mentioned

BETA
xenograft
ChIP
reverse transcription PCR
biopsies
immunoprecipitation
Assay

Software Mentioned

miRanda

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