Sphingosine 1–phosphate signaling induces SNAI2 expression to promote cell invasion in breast cancer cells

Abstract

Epithelial‐mesenchymal transition (EMT) is a critical process implicated in the initial stage of cancer metastasis, which is the major cause of tumor recurrence and mortality. Although key transcription factors that regulate EMT, such as snail family transcriptional repressor 2 (SNAI2), are well characterized, the upstream signaling pathways controlling these transcriptional mediators are largely unknown, which limits therapeutic strategies. Sphingosine 1–phosphate (S1P) is a bioactive lipid mediator, generated by sphingosine kinases (SPHK1 and SPHK2), that mainly exerts its effects by binding to the following 5 GPCRs: S1P1 to S1P5. S1P signaling has been reported to regulate different aspects of cancer progression including cell proliferation, apoptosis, and migration; nevertheless, its role in cancer metastasis, specifically via EMT, is not established. Here we show that SPHK1 expression correlates significantly with EMT score in breast cancer cell lines, and with SNAI2 in patient‐derived breast tumors. Cell‐based assays demonstrate that S1P can rapidly up‐regulate the expression of SNAI2 in breast cancer cells via the activation of cognate receptors S1P2 and S1P3. Knockdown studies suggest that S1P2 and S1P3 mediate this effect by activating myocardin‐related transcription factor A (MRTF‐A) and yes‐associated protein (YAP), respectively. Michigan Cancer Foundation 7 cells stably overexpressing S1P2 or S1P3 exhibit a more invasive phenotype, when compared to control cells. Taken together, our findings suggest that S1P produced by SPHK1 induces SNAI2 expression via S1P2‐YAP and S1P3‐MRTF‐A pathways, leading to enhanced cell invasion. Cumulatively, this study reveals a novel mechanism by which S1P activates parallel pathways that regulate the expression of SNAI2, a master regulator of EMT, and provides new insights into druggable therapeutic targets that may limit cancer metastasis. Wang, W., Hind, T., Lam, B. W. S., Herr, D. R. Sphingosine 1–phosphate signaling induces SNAI2 expression to promote cell invasion in breast cancer cells. FASEB J. 33, 7180–7191 (2019). http://www.fasebj.org

Deciphering the Molecular Basis of Melatonin Protective Effects on Breast Cells Treated with Doxorubicin: TWIST1 a Transcription Factor Involved in EMT and Metastasis, a Novel Target of Melatonin

“…Combination with melatonin (1 nM) further enhanced the anthracyclin stimulatory effect. Importantly, melatonin counteracted the stimulatory effect of doxorubicin over the expression of NME1 (a supressor or metastasis in breast carcinoma) [28]; MUC1 (a p53 supressor) [29]; SNAI2 (involved in invasion and EMT) [30]; BIRC5 (involved in doxorubicin resistance) [31]; and TWIST1 (elevated in invasive breast cancer and involved in EMT [32,33] (Figure 3A).…”

“…Melatonin significantly counteracted the stimulatory effect of doxorubicin on the expression of some genes: MUC1 , (a p53 repressor) overexpressed in cancer [29], SNAI2 , involved in invasion and epithelial to mesenchymal transition [30] and BIRC5 , an inhibitor of apoptosis highly expressed in doxorubicin-resistant cells [31]. The regulation of TWIST1 was the most striking result.…”

Ceramide synthase inhibition by fumonisins: a perfect storm of perturbed sphingolipid metabolism, signaling, and disease

“…How many regulatory processes are altered by fumonisins, and which play the most important roles in disease? In this regard, one must be mindful that new connections between SL and cell regulation are still being discovered and some might be pertinent to fumonisin action, such as: the activation of atypical protein kinase Cs (aPKCs) (PKC and PKC/, which are involved in diverse cellular functions, and can serve as oncogenes or tumor suppressors) by S1P and Sa1P (46); the activation of SNAI2 (a transcriptional regulator of the epithelial to mesenchymal transition) by S1P (47) and its suppression by Cer (48); and others (see Supplement B).…”

Recent advances in the role of sphingosine 1‐phosphate in cancer

“…This is linked with increased invasiveness of MCF-7 breast cancer cells. Finally, SK1 expression correlates with SNAI2 in breast tumours of patients and with EMT score (critical for metastasis) in breast cancer cells [76]. Thus, S1P 2 /YAP/SNAI2 and S1P 3 /MRTF-A/SNAI2 may represent novel points for therapeutic intervention to limit metastasis in breast cancer.…”