Abstract
Aberrant expression of protein arginine methyltransferases (PRMTs) has been implicated in a number of cancers, making PRMTs potential therapeutic targets. But it remains not well understood how PRMTs impact specific oncogenic pathways. We previously identified PRMTs as important regulators of cell growth in neuroblastoma, a deadly childhood tumor of the sympathetic nervous system. Here, we demonstrate a critical role for PRMT1 in neuroblastoma cell survival. PRMT1 depletion decreased the ability of murine neuroblastoma sphere cells to grow and form spheres, and suppressed proliferation and induced apoptosis of human neuroblastoma cells. Mechanistic studies reveal the prosurvival factor, activating transcription factor 5 (ATF5) as a downstream effector of PRMT1-mediated survival signaling. Furthermore, a diamidine class of PRMT1 inhibitors exhibited anti-neuroblastoma efficacy both in vitro and in vivo. Importantly, overexpression of ATF5 rescued cell apoptosis triggered by PRMT1 inhibition genetically or pharmacologically. Taken together, our findings shed new insights into PRMT1 signaling pathway, and provide evidence for PRMT1 as an actionable therapeutic target in neuroblastoma.
Highlights
Overexpression of protein arginine methyltransferases (PRMTs) has been well documented in various cancers and is often correlated with poor prognosis[1]
We found that sphere cells displayed higher levels of PRMT1 and MYCN, as well as Phox2B, a specific biomarker of neuroblast progenitor cells, compared to those in primary tumors, as shown in both Western blot and immunostaining (Fig. 1a, b)
Here we present evidence supporting an essential function of PRMT1-mediated survival pathway in neuroblastoma
Summary
Overexpression of protein arginine methyltransferases (PRMTs) has been well documented in various cancers and is often correlated with poor prognosis[1]. Our previous work demonstrated critical roles of PRMT1 and PRMT5 for neuroblastoma cell growth in part through arginine methylation of MYCN and subsequent enhancement of its stability[3,4]. Amplification of MYCN is found in about 25% of neuroblastoma, the most common extracranial solid tumor of childhood, and correlates with poor outcome[5]. We and others further found a significant correlation between high levels of PRMT1 and unfavorable patient outcome irrespective of MYCN amplification, implying potential MYCN-independent mechanisms for PRMT1 in neuroblastoma[3,6]
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