Dlx-2 is implicated in TGF-β- and Wnt-induced epithelial-mesenchymal, glycolytic switch, and mitochondrial repression by Snail activation

Lee, Su Yeon; Jeon, Hyun Min; Ju, Min Kyung; Jeong, Eunwook; Kim, Cho Hee; Yoo, Mi‐Ae; Park, Hye Gyeong; Kang, Ho Sung

doi:10.3892/ijo.2015.2874

Cited by 34 publications

(43 citation statements)

References 28 publications

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“…Because Dlx-2 induces glycolytic switch by inducing Snail expression [ 37 ], we postulated that Dlx-2 may activate other oncogenic metabolic pathways.…”

Section: Resultsmentioning

confidence: 99%

“…Recently, we showed that distal-less homeobox-2 (Dlx-2), a homeodomain transcription factor involved in embryonic [ 31 , 32 ] and tumor development [ 33 – 36 ], induces EMT and a glycolytic switch by increasing Snail expression [ 37 ]. Because Dlx-2 induces glycolytic switch via Snail induction, we postulated that Dlx-2 may activate other oncogenic metabolic pathways.…”

Section: Introductionmentioning

confidence: 99%

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

Lee

Jeon

et al. 2016

Oncotarget

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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.

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“…Because Dlx-2 induces glycolytic switch by inducing Snail expression [ 37 ], we postulated that Dlx-2 may activate other oncogenic metabolic pathways.…”

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Lee

Jeon

et al. 2016

Oncotarget

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“…Many members of the homeobox gene family have recently been shown to help in facilitating TGF‐β‐induced EMT. Dlx‐2 has also been shown to be involved in TGF‐β and Wnt‐induced EMT in cancers . Also, HOXD3 supports the progression of lung cancer to a certain extent through TGF‐β‐induced EMT .…”

Section: Discussionmentioning

confidence: 99%

HOXD9 promote epithelial‐mesenchymal transition and metastasis in colorectal carcinoma

et al. 2020

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Background: HOXD9, a Hox family member, is involved in cancer growth and metastasis. But, its regulation mechanism at the molecular level particularly in colorectal cancer (CRC), is mostly unknown. Methods: The HOXD9 protein expression levels were analyzed using immunofluorescence, immunohistochemistry (IHC) assays, and western blot. The in vivo and in vitro roles of HOXD9 in CRC were determined using colony formation and EdU incorporation, CCK-8, wound scratch and transwell invasion assay, and animal models. Results: Expression of HOXD9 was higher in CRC than in matched healthy tissues.High expression of HOXD9 has significantly associated with the American Joint Committee on Cancer (AJCC) stages, tumor differentiation, lymph node metastasis, and other serious invasions, and it had a poor prognosis. In vitro, HOXD9 encouraged proliferation, movement and EMT processes in cells of CRC. Also, TGF-β1 promoted the expression of HOXD9 and this effect was dependent on the dose and downregulation of HOXD9 repressed TGF-β1 -induced EMT. In vivo, HOXD9 promoted the invasive and metastasis of CRC cells via orthotopic implantation. Conclusions: The ectopic expression of HOXD9 promoted the invasion metastasis in cells of the colorectal tumor by induction of EMT in vitro and vivo. | 3933 LIU et aL How to cite this article: Liu M, Xiao Y, Tang W, et al. HOXD9 promote epithelial-mesenchymal transition and metastasis in colorectal carcinoma.

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“…In diabetes, renal tubular EMT is an important event in initiating tubulointerstitial fibrosis and contributes to the disease progression and declined renal function 20 21 . Emerging evidences indicate that EMT can be provoked by a variety of stimuli that trigger specific intracellular signalling pathways, such as TGF-β 22 23 . Wnt 24 and Smad2/3 signaling 25 .…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-130b improves renal tubulointerstitial fibrosis via repression of Snail-induced epithelial-mesenchymal transition in diabetic nephropathy

Bai

Geng

Zhou

et al. 2016

Sci Rep

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MicroRNA-130b (miR-130b) downregulation has been identified in diabetes, but the role and mechanisms for miR-130b in mediating renal tubulointerstitial fibrosis in diabetic nephropathy (DN) remain unknown. We demonstrated that plasma miR-130b downregulation exhibited clinical and biological relevance as it was linked to increased serum creatinine, β2-microglobulin and proteinuria, increased Snail expression and tubulointerstitial fibrosis in renal biopsies of DN patients. MiR-130b inhibitor caused Snail upregulation and enhanced molecular features of epithelial-to-mesenchymal transition (EMT) in high glucose (30 mM) cultured NRK-52E cells. In contrast, miR-130b mimic downregulated Snail expression and increased epithelial hallmarks. Notably, Snail was identified as an miR-130b direct target and inversely correlated with E-CADHERIN expression. Furthermore, the miR-130b-dependent effects were due to Snail suppression that in turn deregulated E-CADHERIN, VIMENTIN, COLLAGEN IV and α-smooth muscle actin (α-SMA), key mediators of EMT. These effects were reproduced in streptozotocin-induced diabetic rats. Thus, we propose a novel role of the miR-130b-SNAIL axis in fostering EMT and progression toward increased tubulointerstitial fibrosis in DN. Detection of plasma miR-130b and its association with SNAIL can be extrapolated to quantifying the severity of renal tubulointerstitial fibrosis. Targeting miR-130b could be evaluated as a potential therapeutic approach for DN.

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Dlx-2 is implicated in TGF-β- and Wnt-induced epithelial-mesenchymal, glycolytic switch, and mitochondrial repression by Snail activation

Cited by 34 publications

References 28 publications

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

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

HOXD9 promote epithelial‐mesenchymal transition and metastasis in colorectal carcinoma

MicroRNA-130b improves renal tubulointerstitial fibrosis via repression of Snail-induced epithelial-mesenchymal transition in diabetic nephropathy

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