HnRNP A1 controls a splicing regulatory circuit promoting mesenchymal-to-epithelial transition

Abstract

Epithelial-to-mesenchymal transition (EMT) is an embryonic program used by cancer cells to acquire invasive capabilities becoming metastatic. ΔRon, a constitutively active isoform of the Ron tyrosine kinase receptor, arises from skipping of Ron exon 11 and provided the first example of an alternative splicing variant causatively linked to the activation of tumor EMT. Splicing of exon 11 is controlled by two adjacent regulatory elements, a silencer and an enhancer of splicing located in exon 12. The alternative splicing factor and oncoprotein SRSF1 directly binds to the enhancer, induces the production of ΔRon and activates EMT leading to cell locomotion. Interestingly, we now find an important role for hnRNP A1 in controlling the activity of the Ron silencer. HnRNP A1 is able to antagonize the binding of SRSF1 and prevent exon skipping. Notably, hnRNP A1, by inhibiting the production of ΔRon, activates the reversal program, namely the mesenchymal-to-epithelial transition, which instead occurs at the final metastasis sites. Also, hnRNP A1 affects Ron splicing by regulating the expression level of hnRNP A2/B1, which similarly to SRSF1 can promote ΔRon production. These results shed light on how splicing regulation contributes to the tumor progression and provide potential targets to develop anticancer therapies.

The role of splicing factors in deregulation of alternative splicing during oncogenesis and tumor progression

“…As a result the cells undergo mesenchymal-toepithelial transition (MET), which leads to the establishment of secondary tumors. 97 The fact that hnRNP A1 and SRSF1 act in opposite manners on RON alternative splicing supports the view that tight regulation of splicing factors is necessary for metastasis of cancer cells.…”

Cell type-restricted activity of hnRNPM promotes breast cancer metastasis via regulating alternative splicing

“…In conclusion, dysregulation of alternative splicing has been increasingly recognized in cancer-related pathways (Valacca et al 2010;Anczukow et al 2012;Das et al 2012;Bonomi et al 2013). It is thus critical to investigate the functional significance of splicing regulation in the context of cancer.…”

Molecular basis of shikonin-induced immunogenic cell death: insights for developing cancer therapeutics

“…In normal somatic tissues, epithelial-to-mesenchymal transition (EMT) activity is not only instrumental in facilitating wound-healing activity but also in promoting tissue fibrosis [30][31][32] . In addition, hnRNPA1 has been shown to play an important role in control of specific splicing activity of tyrosine kinase receptor (Ron), and can thus further promote the MET activity [33] . Taking these findings together, we contemplate that SK-induced EMT and the related changes in microRNA expression in vivo may also reflect the dysfunction of hnRNPA1 activity [7] .…”