HDAC4/MybL1/YAP novel signaling axis is required for pancreatic cancer metastasis to the liver

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 1 (MybL1) and YAP. Mechanistic studies show that HDAC4 regulates transcription of YAP through up-regulating MybL1 expression. Comparable results were observed in colon and prostate cancers. ATAC-seq studies show that inhibition of HDAC4 causes chromatin remodeling in the YAP promoter region and reduces accessibility to the binding sites of multiple transcription factors, including those of MybL1. Pharmacological or molecular inhibition of YAP significantly decreases PDAC metastasis in vivo. Imaging Mass Cytometry (IMC) reveals no significant changes in immune cells, but a notable shift in the distribution patterns of cancer-associated hepatic stellate cells in the metastatic niche, when YAP is ablated in the cancer cells. The results demonstrate a novel metastasis-driving cell signaling pathway mediated by the functional interaction between HDAC4 and MybL1, which regulates YAP expression and metastasis.