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

Abstract

The p14ARF protein is a well‐known regulator of p53‐dependent and p53‐independent tumor‐suppressive activities. In unstressed cells, p14ARF is predominantly sequestered in the nucleoli, bound to its nucleolar interaction partner NPM. Upon genotoxic stress, p14ARF undergoes an immediate redistribution to the nucleo‐ and cytoplasm, where it promotes activation of cell cycle arrest and apoptosis. Here, we identify p14ARF 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 p14ARF. In the absence of cellular stress, these arginines are crucial for nucleolar localization of p14ARF. Genotoxic stress causes augmented interaction between PRMT1 and p14ARF, accompanied by arginine methylation of p14ARF. PRMT1‐dependent NLS/NoLS methylation promotes the release of p14ARF from NPM and nucleolar sequestration, subsequently leading to p53‐independent apoptosis. This PRMT1‐p14ARF 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 p14ARF’s stress‐induced tumor‐suppressive function.

PRMT1 Regulates EGFR and Wnt Signaling Pathways and Is a Promising Target for Combinatorial Treatment of Breast Cancer

“…PRMT1 interacts with the progesterone receptor in the nucleus of breast cancer cells [ 39 ]. In addition, PRMT1 is expressed in both the cytosol and the nucleus in renal [ 46 , 47 ] and pancreatic [ 48 ] carcinomas. We also detected PRMT1 at the plasma membrane, preferentially in the ER-negative BC subtypes, possibly since it interacts with some transmembrane receptors such as EGFR [ 20 , 21 ] or IGF-1R [ 49 ].…”

Epigenetic drug screening defines a PRMT5 inhibitor–sensitive pancreatic cancer subtype

“…PRMT1 was recently shown to be a potential therapeutic target in PDAC (45,49). However, in cases in which PRMT1 inhibitors were combined with chemotherapy, like gemcitabine, clear evidence demonstrates the need to stratify for responders (50). PRMT5 is the primary type II molecule methylating arginines of histones and other proteins.…”

“…Viability assay, GI 50 and AUC calculations, caspase-3/7 assay, clonogenic assay, flow cytometry, and drug synergy calculations. See the Supplemental Methods for this information.…”

It’s Getting Complicated—A Fresh Look at p53-MDM2-ARF Triangle in Tumorigenesis and Cancer Therapy

“…ARF-mediated apoptosis relies on ARF's ability to localize to mitochondria, and is regulated by the interaction between ARF and mitochondrial protein p32 (Itahana and Zhang, 2008). A recent study elucidated the underlying mechanism by showing that, under genotoxic stresses, PRMT1 (protein arginine methyltransferase 1) methylates arginine residues within the NLS/NoLS of ARF, resulting in the release of ARF from NPM and increased interaction between ARF and p32 (Repenning et al, 2021). Mitochondria-bound ARF induces apoptosis by activating BAK instead of BAX, suggesting a tightly-regulated process controlling ARF-mediated apoptosis in the absence of p53 (Müer et al, 2012).…”