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

// Su Yeon Lee 1 , Hyun Min Jeon 1 , Min Kyung Ju 1 , Eui Kyong Jeong 1 , Cho Hee Kim 1, * , Hye Gyeong Park 2 , Song Iy Han 3 , Ho Sung Kang 1 1 Department of Molecular Biology, College of Natural Sciences, Pusan 609-735, Korea 2 Nanobiotechnology Center, Pusan National University, Pusan 609-735, Korea 3 The Division of Natural Medical Sciences, College of Health Science, Chosun University, Gwangju 501-759, Korea * Present address: DNA Identification Center, National Forensic Service, Seoul 158-707, Korea Correspondence to: Ho Sung Kang, e-mail: hspkang@pusan.ac.kr Keywords: Dlx-2, GLS1, Snail, epithelial-mesenchymal transition, glycolytic switch Received: May 23, 2015 Accepted: January 02, 2016 Published: January 11, 2016 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.