# The long noncoding RNA VIM-AS1 and nucleoporin Nup358/RanBP2 regulate SMAD nuclear accumulation during TGF-β signaling

## TL;DR

This paper shows how a long noncoding RNA, VIM-AS1, interacts with a nucleoporin to enhance TGF-β signaling by promoting SMAD nuclear accumulation.

## Contribution

The study reveals a novel mechanism where VIM-AS1 v.2 interacts with Nup358/RanBP2 to enhance SMAD nuclear accumulation during TGF-β signaling.

## Key findings

- VIM-AS1 v.2 enhances TGF-β signaling by interacting with Nup358/RanBP2.
- VIM-AS1 v.2 increases tumor cell invasion and motility but does not affect TGF-β's antiproliferative actions.
- Silencing VIM-AS1 sensitizes cancer cells to chemotherapeutic agents.

## Abstract

The transforming growth factor β (TGF-β) pathway is a developmental signaling network that regulates tissue homeostasis and malfunctions in human diseases, including cancer. TGF-β signals via two receptors, which activate SMAD and alternative signaling pathways. We show that TGF-β induces the expression of the mammalian long noncoding RNA (lncRNA) VIM-AS1 (Vimentin antisense RNA1) variant-2 (v.2) via a transcriptional SMAD-GATA6-SPI1 complex. VIM-AS1 v.1 and v.2 localize in different cell compartments, including the nuclear border. Unbiased whole transcriptomic analysis and functional gain and loss of function assays establish that VIM-AS1 v.2 enhances TGF-β signaling. Mechanistically, VIM-AS1 v.2 interacts with the nucleoporin Nup358/RanBP2, contributing to the binding of Nup358/RanBP2 to SMAD2/3 and enhancing SMAD nuclear accumulation. In the context of cancer biology, VIM-AS1 did not affect the antiproliferative actions of TGF-β, yet had an impact on the epithelial–mesenchymal transition gene program, and increased the invasion and motility of tumor cells, whereas its silencing sensitized cancer cells to chemotherapeutic agents. The molecular mechanism highlights how a lncRNA can modulate the nuclear pore’s capacity to import SMAD complexes, by facilitating their capture by Nup358/RanBP2 and thereby enhancing nuclear accumulation of SMADs with distinct isoform composition, thus promoting selectively TGF-β signaling responses.

Graphical Abstract