Snail nuclear transport: The gateways regulating epithelial-to-mesenchymal transition?

Abstract

Epithelial-to-mesenchymal transition (EMT) and the reverse process (MET) plays central role in organ developmental biology. It is a fine tuned process that when disturbed leads to pathological conditions especially cancers with aggressive and metastatic behavior. Snail is an oncogene that has been well established to be a promoter of EMT through direct repression of epithelial morphology promoter E-cadherin. It can function in the nucleus, in the cytosol and as discovered recently, extracellularly through secretory vesicular structures. The intracellular transport of snail has for long been shown to be regulated by the nuclear pore complex. One of the Karyopherins, importin alpha, mediates snail import, while importin beta/exportin 1 (Xpo1) or chromosome maintenance region 1 (CRM1) is its major nuclear exporter. A number of additional biological regulators are emerging that directly modulate Snail stability by altering its subcellular localization. These observations indicate that targeting the nuclear transport machinery could be an important and as of yet, unexplored avenue for therapeutic intervention against the EMT processes in cancer. In parallel, a number of novel agents that disrupt nuclear transport have recently been discovered and are being explored for their anti-cancer effects in the early clinical settings. Through this review we provide insights on the mechanisms regulating snail subcellular localization and how this impacts EMT. We discuss strategies on how the nuclear transport function can be harnessed to rein in EMT through modulation of snail signaling.

TRIM16 suppresses the progression of prostate tumors by inhibiting the Snail signaling pathway

“…It codes for a 29.1 kDa protein composed of 264 amino acids. This protein contains three classic zinc fingers and one atypical zinc finger (26). The zinc-finger transcription factor Snail belongs to the Snail superfamily of transcriptional repressors.…”

“…The zinc-finger transcription factor Snail belongs to the Snail superfamily of transcriptional repressors. The Snail family of transcription factors has previously been demonstrated to play a role in the differentiation of epithelial cells into mesenchymal cells (also known as EMT) during embryonic development (26). Snail is a strong repressor of the transcription of the E-cadherin gene and is considered as a marker of malignancy (26).…”

Left-right axis asymmetry determining human Cryptic gene is transcriptionally repressed by Snail

“…It is involved in the movement of cells in the developing embryo and its aberrant activation leads to several metastatic cancers [25]. As a transcription factor, Snail represses the expression of epithelial markers like E-cadherin, thereby conferring motility to cells.…”

The regulation of snail: on the ubiquitin edge

“…Clinically, Snail expression is associated with resistance to chemotherapy, decreased survival, high recurrence rates and a poor prognosis [11][12][13] . In accordance with its profound role in development, Snail has a short half-life and is tightly regulated by extracellular signaling, induced phosphorylation and degradation through ubiquitination [14] .…”