The PRMT5-LSD1 axis confers Slug dual transcriptional activities and promotes breast cancer progression

Jianchao Zhang, Xiaokai Fan, Yunfan Zhou, Liang Chen, Hai Rao

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Downregulation of epithelial markers and upregulation of mesenchymal markers are the characteristics of the epithelial to mesenchymal transition (EMT) program, which provides the metastatic advantage of breast cancer. However, the mechanism underlying the switch of EMT markers remains poorly understood. Methods: In this study, we used the affinity purification and mass spectrometry coupled approach to identify the interactome of Slug. CoIP, GST-pulldown, ChIP, Re-ChIP, qPCR and Immunoblot were used to investigate the underlying mechanism of Slug-PRMT5-LSD1 complex. The role of PRMT5 and LSD1 in breast cancer progression was evaluated both in vivo and in vitro. Results: Here we found that the transcription factor Slug associates with PRMT5 and LSD1 in a complex and facilitates the breast cancer invasion in vitro. Mechanistically, PRMT5 and LSD1 work with Slug to exert dual transcriptional activities to inhibit E-cadherin expression by PRMT5-catalyzed H4R3me2s and LSD1-mediated demethylation of H3K4me2 on the E-cadherin (CDH1) promoter, and activate vimentin (VIM) expression via PRMT5-driven H3R2me2s and LSD1-mediated removal of H3K9me2. Importantly, PRMT5 and LSD1 are coordinately expressed in breast cancer patients and pharmacologic perturbation of both PRMT5 and LSD1 shows a synergetic effect on the inhibition of breast tumor growth and metastasis in vivo. Conclusions: Our study suggests that PRMT5 and LSD1 function as a dual epigenetic modifier to promote Slug induced EMT program, suggesting that the inhibition of PRMT5 and LSD1 presents a potential therapeutic strategy against cancer metastasis.

Original languageEnglish (US)
Article number191
JournalJournal of Experimental and Clinical Cancer Research
Volume41
Issue number1
DOIs
StatePublished - Dec 2022
Externally publishedYes

Keywords

  • Demethylation
  • EMT
  • LSD1
  • Metastasis and breast cancer
  • Methylation
  • PRMT5
  • Slug

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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