PRMT1 is a novel molecular therapeutic target for clear cell renal cell carcinoma

Abstract

Background and Objective: Epigenetic alterations are common events in clear cell renal cell carcinoma (ccRCC), and protein arginine methyltransferase 1 (PRMT1) is an important epigenetic regulator in cancers. However, its role in ccRCC remains unclear. Methods: We investigated PRMT1 expression level and its correlations to clinicopathological factors and prognosis in ccRCC patients based on ccRCC tissue microarrays (TMAs). Genetic knockdown and pharmacological inhibition using a novel PRMT1 inhibitor DCPT1061 were performed to investigate the functional role of PRMT1 in ccRCC proliferation. Besides, we confirmed the antitumor effect of PRMT1 inhibitor DCPT1061 in ccRCC cell-derived tumor xenograft (CDX) models as well as patient-derived tumor xenograft (PDX) models. Results: We found PRMT1 expression was remarkably upregulated in tumor tissues and associated with poor pathologic characters and outcomes of ccRCC patients. Furthermore, genetic knockdown and pharmacological inhibition of PRMT1 by a novel potent inhibitor DCPT1061 dramatically induced G1 cell cycle arrest and suppressed ccRCC cell growth. Mechanistically, RNA sequencing and further validation identified Lipocalin2 (LCN2), a secreted glycoprotein implicated in tumorigenesis, as a crucial regulator of ccRCC growth and functional downstream effector of PRMT1. Epigenetic silencing of LCN2 autocrine secretion by PRMT1 deficiency decreased downstream p-AKT, leading to reduced p-RB and cell growth arrest through the neutrophil gelatinase associated lipocalin receptor (NGALR). Moreover, PRMT1 inhibition by DCPT1061 not only inhibited tumor growth but also sensitized ccRCC to sunitinib treatment in vivo by attenuating sunitinib-induced upregulation of LCN2-AKT-RB signaling. Conclusion: Taken together, our study revealed a PRMT1-dependent epigenetic mechanism in the control of ccRCC tumor growth and drug resistance, indicating PRMT1 may serve as a promising target for therapeutic intervention in ccRCC patients.

PRMT1 regulates EGFR and Wnt signaling pathways and is a promising target for combinatorial treatment of breast cancer

“…We found that PRMT1 depletion (i) decreased BC cell viability, (ii) blocked their clonogenic potential, and (iii) induced DNA damage and apoptosis in various cell lines of different BC subtypes. This is in accordance with previous reports in TNBC (20,33,43,44) and luminal (35,44,45) BC cell lines as well as cell lines of other cancer types (22,(46)(47)(48)(49). We next addressed the question whether the enzymatic activity of PRMT1 was required for BC cell survival.…”

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

“…We found that PRMT1 depletion (i) decreased the cell viability, (ii) blocked their clonogenic potential, and (iii) induced DNA damage and apoptosis in various cell lines of different BC subtypes. This is in accordance with previous reports in TNBC [ 21 , 37 , 50 , 51 ] and luminal [ 39 , 51 , 52 ] BC cell lines as well as cell lines of other cancer types [ 23 , 46 , 53 , 54 , 55 ]. We next addressed the question whether the enzymatic activity of PRMT1 was required for BC cell survival.…”

“…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 ].…”

DNA replication stress stratifies prognosis and enables exploitable therapeutic vulnerabilities of HBV-associated hepatocellular carcinoma: an in silico strategy towards precision oncology

“…PRMT1 can promote the tumorigenesis and progression of HCC through activating STAT3, TGF-β1/Smad and HNF4α pathways [51][52][53] . Moreover, it has recently been reported that genetic knockdown and pharmacological inhibition of PRMT1 by DCPT1061, a novel potent inhibitor, drastically induced G1-phase cell cycle arrest and suppressed cell growth of clear cell renal cell carcinoma 54 ; another PRMT1 inhibitor (GSK3368715) was capable of impairing replication restart of pancreatic ductal adenocarcinoma, thus inhibiting tumor growth 55 . The casein kinase 1 delta (CK1δ, CSNK1D) is a member of serine/threonine protein kinase family that comprises of six isoforms (i.e., α, δ, ε, γ1, γ2 and γ3) that were involved in several signaling pathways (e.g., Hedgehog, Wnt, and Hippo), and mediates numerous cellular processes (e.g., DNA replication, DDR, RNA metabolism, membrane trafficking, cytoskeleton maintenance, and circadian rhythm) 56 .…”