The arginine methyltransferase PRMT1 regulates IGF-1 signaling in breast cancer

Ali Choucair,Soleilmane Omarjee,Olivier Trédan,Elisabetta Marangoni,Loay Kassem,Thuy Ha Pham,Muriel Le Romancer,Laura Corbo,Isabelle Treilleux,Julien Jacquemetton,Juliette Rambaud

doi:10.1038/s41388-019-0694-9

Abstract

Aside from its well-known nuclear routes of signaling, estrogen also mediates its effects through cytoplasmic signaling. Estrogen signaling involves numerous posttranslational modifications of its receptor ERα, the best known being phosphorylation. Our research group previously showed that upon estrogen stimulation, ERα is methylated on residue R260 and forms the mERα/Src/PI3K complex, central to the rapid transduction of nongenomic estrogen signals. Regulation of ERα signaling via its phosphorylation by growth factors is well recognized, and we wondered whether they could also trigger ERα methylation (mERα). Here, we found that IGF-1 treatment of MCF-7 cells induced rapid ERα methylation by the arginine methyltransferase PRMT1 and triggered the binding of mERα to IGF-1R. Mechanistically, we showed that PRMT1 bound constitutively to IGF-1R and that PRMT1 became activated upon IGF-1 stimulation. Moreover, we found that expression or pharmacological inhibition of PRMT1 impaired mERα and IGF-1 signaling. Our findings were substantiated in a cohort of breast tumors in which IGF-1R expression was positively correlated with ERα/Src and ERα/PI3K expression, hallmarks of nongenomic estrogen signaling, reinforcing the link between IGF-1R and mERα. Altogether, these results provide a new insight into ERα and IGF-1R interference, and open novel perspectives for combining endocrine therapies with PRMT1 inhibitors in ERα-positive tumors.

Highlights

Supplementary information The online version of this article contains supplementary material, which is available to authorized users.Cambridge, Cambridge CB2 0RE, UK 5 Clinical Oncology Department, Faculty of Medicine, CairoUniversity, Cairo, Egypt 6 Oncology Department, Centre Leon Bérard, Lyon, France 7 Translational Research Department, Institut Curie, 75005Paris, France 8 Pathology Department, Centre Leon Bérard, Lyon, FranceBreast cancer is the second most common cancer affecting women worldwide after lung cancer
IGF-1 stimulation fostered the interaction between mERα and insulin-like growth factor 1 receptor (IGF-1R) (Fig. 1d), indicating that IGF-1R may be implicated in the IGF-1/mERα signaling pathway, corroborating a previous study which reported that treatment of cells with IGF-1 induces a partial relocalization of ERα into the cytoplasm [11]
With the finding that ERα may bind IGF-1R at the plasma membrane via the adaptor insulin receptor substrate 1 (IRS1) [20], we studied the involvement of IRS1 in IGF-1-induced ERα methylation, but revealed that IRS1 knockdown via siRNA had no effect on mERα (Supplementary Fig. S8)

Summary

Introduction

University, Cairo, Egypt 6 Oncology Department, Centre Leon Bérard, Lyon, France 7 Translational Research Department, Institut Curie, 75005. Patients are often diagnosed in the early and curable stages, the treatment of metastatic breast cancer remains a major clinical challenge. ERα-positive patients are treated with hormonotherapy, though acquired resistance to hormonal treatments has emerged, highlighting the need for novel strategies to improve clinical outcome [1]. ERα signaling is quite complex and involves many actors, from its typical genomic/nuclear pathway and from its nongenomic pathway [2, 3], only the nuclear ERα status is currently taken into account in the decision-making process associated with treatment management. Estrogen induces the interaction of ERα with Src, PI3K and other proteins to form a large complex that activates downstream proliferative signaling pathways such as

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