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The Use of Reverse Phase Protein Arrays RPPA to Explore Protein Expression Variation within Individual Renal Cell Cancers
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PRMT1 is a novel molecular therapeutic target for clear cell renal cell carcinoma

Jianfeng Wang1, Chen Wang2,3, Pan Xu2,3

  • 1Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China.

Theranostics
|April 16, 2021
PubMed

Insights

Protein arginine methyltransferase 1 (PRMT1) is upregulated in clear cell renal cell carcinoma (ccRCC), driving tumor growth and drug resistance. Inhibiting PRMT1 with DCPT1061 suppressed ccRCC progression and sensitized tumors to sunitinib.

Area of Science:

  • Oncology
  • Epigenetics
  • Molecular Biology

Background:

  • Epigenetic alterations are hallmarks of clear cell renal cell carcinoma (ccRCC).
  • Protein arginine methyltransferase 1 (PRMT1) is an epigenetic regulator implicated in various cancers, but its specific role in ccRCC is not well-defined.
  • Understanding PRMT1's function is crucial for developing targeted therapies for ccRCC.

Purpose of the Study:

  • To investigate the expression and functional role of PRMT1 in ccRCC.
  • To evaluate the therapeutic potential of a novel PRMT1 inhibitor, DCPT1061, in ccRCC models.
  • To elucidate the molecular mechanisms underlying PRMT1's effects on ccRCC growth and drug resistance.

Main Methods:

  • Analysis of PRMT1 expression in ccRCC tissue microarrays (TMAs) and correlation with clinicopathological factors and prognosis.
  • In vitro studies involving genetic knockdown and pharmacological inhibition of PRMT1 using DCPT1061 to assess effects on ccRCC cell proliferation.
  • In vivo validation of DCPT1061's antitumor efficacy in cell-derived tumor xenograft (CDX) and patient-derived tumor xenograft (PDX) models.
  • RNA sequencing and mechanistic studies to identify downstream effectors of PRMT1 signaling.

Main Results:

  • PRMT1 expression is significantly upregulated in ccRCC tissues and correlates with adverse clinicopathological features and poor patient outcomes.
  • PRMT1 inhibition, via genetic knockdown or DCPT1061 treatment, induced G1 cell cycle arrest and suppressed ccRCC cell growth.
  • PRMT1 epigenetically regulates Lipocalin 2 (LCN2) autocrine secretion, impacting the LCN2-AKT-RB signaling pathway, which is critical for ccRCC proliferation.
  • DCPT1061 treatment inhibited tumor growth in vivo and enhanced sensitivity to sunitinib by modulating the LCN2-AKT-RB pathway.

Conclusions:

  • PRMT1 plays a critical role in ccRCC tumorigenesis and progression.
  • PRMT1 inhibition, particularly with DCPT1061, demonstrates significant antitumor activity in ccRCC.
  • The PRMT1-LCN2-AKT-RB axis represents a novel therapeutic target for ccRCC, offering potential for combination therapies to overcome drug resistance.
Keywords:
clear cell renal cell carcinomalipocalin2 (LCN2)protein arginine methyltransferase 1sunitinibtherapeutic

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