PRMT1 promotes the tumor suppressor function of p14 ARF and is indicative for pancreatic cancer prognosis

Abstract

The p14(ARF) protein is a well-known regulator of p53-dependent and p53-independent tumor-suppressive activities. In unstressed cells, p14(ARF) is predominantly sequestered in the nucleoli, bound to its nucleolar interaction partner NPM. Upon genotoxic stress, p14(ARF) undergoes an immediate redistribution to the nucleo- and cytoplasm, where it promotes activation of cell cycle arrest and apoptosis. Here, we identify p14(ARF) as a novel interaction partner and substrate of PRMT1 (protein arginine methyltransferase 1). PRMT1 methylates several arginine residues in the C-terminal nuclear/nucleolar localization sequence (NLS/NoLS) of p14(ARF) . In the absence of cellular stress, these arginines are crucial for nucleolar localization of p14(ARF) . Genotoxic stress causes augmented interaction between PRMT1 and p14(ARF) , accompanied by arginine methylation of p14(ARF) . PRMT1-dependent NLS/NoLS methylation promotes the release of p14(ARF) from NPM and nucleolar sequestration, subsequently leading to p53-independent apoptosis. This PRMT1-p14(ARF) cooperation is cancer-relevant and indicative for PDAC (pancreatic ductal adenocarcinoma) prognosis and chemotherapy response of pancreatic tumor cells. Our data reveal that PRMT1-mediated arginine methylation is an important trigger for p14(ARF) 's stress-induced tumor-suppressive function.