Abstract 1485: Elucidating the role of VGLL1 in pancreatic cancer tumorigenesis
Authors: Sonnemann Heather M. , Pazdrak Barbara , Nassif Barbara , Sun Yimo , Elzohary Lama , Talukder Amjad , Katailiha Arjun , Bentebibel Salah-Eddine , Diab Adi , Lizee Gregory 
Published: June 2023

Abstract
Vestigial-like 1 (VGLL1) is a co-transcriptional activator that binds to TEA domain-containing transcription factors (TEADs). Its expression is upregulated in a variety of cancers and is correlated with decreased overall patient survival. In normal tissues, VGLL1 is most highly expressed in placental trophoblast cells, which share attributes of rapid cellular proliferation and invasion with cancer cells. Binding of VGLL1 to TEADs shows structural similarity to co-transcriptional activators in the Hippo pathway, yes-associated protein 1 (YAP) and WW Domain containing transcription regulator 1 (WWTR1/TAZ). YAP/TAZ has been implicated in tumorigenesis in many cancer types, and this structural relationship has provided insights into the functional role of VGLL1. The impact of VGLL1 expression in pancreatic cancer has not been fully elucidated and no VGLL1-targeted therapy currently exists.
The aim of this study was to evaluate the function and downstream targets of VGLL1 in pancreatic cancer cells. Ectopic expression of VGLL1 in human pancreatic cell lines PANC1 and SU8686 stimulated cancer cell proliferation and invasion, consistent with findings from other cancer types. ChIP-seq and Nanostring assays were also performed to identify VGLL1 downstream target genes and pathways. Interestingly, analysis of ChIP-seq data from VGLL1-transduced PANC1 cells identified four novel transcription factors with a VGLL1 binding motif, in addition to TEAD4 which has been previously reported. Furthermore, gene array analysis showed approximately 150 differentially expressed genes in mouse pancreatic cancer cells transduced with VGLL1, including genes involved in regulation of cell cycle and apoptosis. Ectopic VGLL1 expression resulted in the increased expression of AP-1, MMP9, and VEGF, genes associated with cancer progression. Furthermore, VGLL1 decreased the expression of cyclin-dependent kinase inhibitors such as p15, p16 and p21 that are associated with reduced cancer cell proliferation. To identify potential regulatory features of VGLL1, we performed mass spectrometry to identify phosphorylation sites and potential binding partners. Our preliminary data suggests that 14-3-3 binds to VGLL1, an intriguing finding since 14-3-3 is also known to regulate YAP/TAZ by sequestering it in the cytoplasm upon being phosphorylated. Our results demonstrate that VGLL1 interacts with specific transcription factors such as TEAD4 in pancreatic cancer cells to modulate the expression of genes expected to promote cell proliferation and invasion. In addition, we have identified a potential regulatory molecule for VGLL1 that plays a critical role in inhibiting other co-transcription activators from translocating into the nucleus. It is hoped that this work will set the stage for the development of VGLL1-targeted therapies with which to treat patients with pancreatic cancer.
Citation Format: Heather M. Sonnemann, Barbara Pazdrak, Barbara Nassif, Yimo Sun, Lama Elzohary, Amjad Talukder, Arjun Katailiha, Salah-Eddine Bentebibel, Adi Diab, Gregory Lizee. Elucidating the role of VGLL1 in pancreatic cancer tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1485.