Nuclear VAV1 increases GLI1-dependent transcription in pancreatic cancer cells

TL;DR

This study shows that nuclear VAV1 promotes cancer growth in pancreatic cells by enhancing GLI1 activity and BCL2 expression.

Contribution

The study reveals a novel role for nuclear VAV1 in regulating GLI1-dependent transcription in pancreatic cancer.

Findings

Nuclear VAV1 increases GLI transcriptional activity without changing GLI factor expression.

VAV1 interacts with GLI1 and is required for BCL2 expression and promoter activity.

VAV1 is necessary for GLI1 and PCAF binding to the BCL2 promoter region.

Abstract

The oncogenic role of VAV1, a GTPase guanine nucleotide exchange factor (GEF) with cytoplasmic and nuclear localizations, has been previously reported in multiple malignancies. Most of the mechanisms underlying this pro-tumoral activity have been linked to the cytoplasmic expression of this GEF. To date, the contribution of nuclear VAV1 to cancer development remains poorly understood. Here, using models of pancreatic ductal adenocarcinomas (PDAC), the most common subtype of pancreatic cancer, we provide evidence of a novel mechanism driving oncogenic gene expression in PDAC cells that is regulated by nuclear VAV1. We show that VAV1 wild-type, unlike its mutant lacking the nuclear localization signal (NLS), localizes to the nucleus of PDAC cells where it increases GLI transcriptional activity without affecting the expression of GLI factors (GLI1, GLI2 and GLI3). Interestingly, this VAV1 NLS-deficient mutant loses interaction with Importin b1 but maintains ability to activate RAC1. Further analysis showed that VAV1 and GLI1 endogenously interact in PDAC cells, and knockdown of VAV1 reduces the expression of a set of GLI target genes including BCL2. We found VAV1 bound to the GLI binding motif present within the BCL2 promoter region and demonstrate the requirement of VAV1 to maintain BCL2 expression and promoter activity. Finally, we showed that VAV1 is necessary for the binding of GLI1 and its coactivator the histone acetyltransferase PCAF to this regulatory element. Taken together, our data supports a role for VAV1 in GLI1 transcriptional regulation, elucidating a new mechanism of function for nuclear VAV1 in PDAC cells.

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