HDAC4/MybL1/YAP novel signaling axis is required for pancreatic cancer metastasis to the liver
Mouad Edderkaoui, Omer H.M. Elmadbouh, Adrian Lim, Yan Ou, Dina Hauptschein, Ankita Guha, Abdo Darwish, Vinicius F. Calsavara, Ramachandran Murali, Neil Bhowmick, Arsen Osipov, Angela J. Mathison, Raul Urrutia, Qiang Wang, Stephen J. Pandol
TL;DR
This study identifies a new signaling pathway involving HDAC4, MybL1, and YAP that drives pancreatic cancer metastasis to the liver.
Contribution
The paper discovers a novel HDAC4/MybL1/YAP signaling axis critical for pancreatic cancer metastasis.
Findings
HDAC4 and YAP are highly expressed in aggressive pancreatic cancer with metastasis.
HDAC4 inhibition reduces cancer cell migration and YAP expression through MybL1 regulation.
YAP inhibition significantly decreases pancreatic cancer metastasis in mouse models.
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest forms of human malignancy, and there is an urgency to develop more effective therapy. We previously showed that Metavert, a dual inhibitor of glycogen synthase kinase 3-beta (GSK-3β) and histone deacetylases (HDACs) prevents pancreatic ductal adenocarcinoma (PDAC) metastasis. In this study, we investigated the mechanisms that mediate metastasis and the roles of GSK-3β, HDACs, and Yes-associated protein (YAP) in this process. We found that HDAC4 and YAP are highly expressed in PDAC from patients with rapid disease progression and metastasis compared to those with prolonged recurrence-free survival. Pan-HDAC inhibition decreases metastasis in the splenic PDAC metastatic mouse model. Inhibition of HDAC4 reduces migration of cancer cells and decreases the mRNA and protein levels of transcription factor MYB Proto-Oncogene Like…
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Taxonomy
TopicsHippo pathway signaling and YAP/TAZ · Histone Deacetylase Inhibitors Research · Immune cells in cancer