Protein Phosphatase 2 Is Required for Metastatic Dormancy and Is Regulated by Histone Demethylase KDM5A

Metastatic cells migrate from primary tumors and persist as dormant clusters. The mechanisms that allow these cells to escape their dormant state are an area of intense investigation. Protein phosphatase 2 (PPP2) is a tumor suppressor that dephosphorylates protein kinases involved in proliferation and metastasis. Increased PPP2 expression has been associated with progression-free survival in head and neck cancer (HNSC). A frequently altered epigenetic modifier in HNSC is the lysine demethylase KDM5A. KDM5A catalyzes demethylation of histone H3K4, resulting in chromatin compaction and repression of target genes. Despite the frequency of altered KDM5A expression in HNSC, the mechanism by which it regulates the progression of these cancers is unclear. Our present study demonstrates, using novel genetically engineered models, that PPP2 inhibition results in escape from metastatic dormancy via increased target protein phosphorylation, IL10 expression, and lymphocyte depletion. Genomic analysis demonstrated that KDM5A directly targets the PPP2 catalytic subunit. Genetic inhibition of KDM5A expression in vivo promotes HNSC metastatic dormancy via decreased IL10 expression. CRISPR-mediated ablation of KDM5A expression inhibits the proliferation of HNSC lines, and treatment with a small molecule KDM5A inhibitor results in the death of these cells. We concluded that PPP2 is required for HNSC metastatic dormancy and is regulated by KDM5A.