Sulforaphane inhibits PRMT5 and MEP50 function to suppress the mesothelioma cancer cell phenotype

Our plain-English summary of Sulforaphane inhibits PRMT5 and MEP50 function to suppress the mesothelioma cancer cell phenotype, by G. Ezeka, G. Adhikary, S. Kandasamy, et al (Molecular Carcinogenesis, 2021).

The study

• Authors: G. Ezeka, G. Adhikary, S. Kandasamy, J.S. Friedberg, R.L. Eckert
• Journal: Molecular Carcinogenesis
• Published: 2021;60(7):429-439
• Cited by: 9 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Mesothelioma is a highly aggressive cancer of the mesothelial lining that is caused by exposure to asbestos. Surgical resection followed by chemotherapy is the current treatment strategy, but this is marginally successful and leads to drug-resistant disease. We are interested in factors that maintain the aggressive mesothelioma cancer phenotype as therapy targets. Protein arginine methyltransferase 5 (PRMT5) functions in concert with the methylosome protein 50 (MEP50) cofactor to catalyze symmetric dimethylation of key arginine resides in histones 3 and 4 which modifies the chromatin environment to alter tumor suppressor and oncogene expression and enhance cancer cell survival. Our studies show that PRMT5 or MEP50 loss reduces H4R3me2s formation and that this is associated with reduced cancer cell spheroid formation, invasion, and migration. Treatment with sulforaphane (SFN), a diet-derived anticancer agent, reduces PRMT5/MEP50 level and H4R3me2s formation and suppresses the cancer phenotype. We further show that SFN treatment reduces PRMT5 and MEP50 levels and that this reduction is required for SFN suppression of the cancer phenotype. SFN treatment also reduces tumor formation which is associated with reduced PRMT5/MEP50 expression and activity. These findings suggest that SFN may be a useful mesothelioma treatment agent that operates, at least in part, via suppression of PRMT5/MEP50 function.

© 2021 Wiley Periodicals LLC.

In plain English

This laboratory study used two human mesothelioma cell lines, Meso-1 (from peritoneal mesothelioma) and NCI-Meso-17 (from pleural mesothelioma), and mice carrying tumors grown from Meso-1 cells. It did not study asbestos exposure. The authors examined two proteins, PRMT5 and its partner MEP50, which place a chemical mark (H4R3me2s) on histones, the proteins that package DNA. In Meso-1 cells, lowering PRMT5, or PRMT5 and MEP50 together, reduced this mark. It was also associated with reduced cell growth, sphere formation, invasion and migration. Blocking PRMT5 with a drug, GSK-3326595, also reduced the mark and cell growth. Sulforaphane, a compound the article describes as abundant in cruciferous vegetables, was given at 20 μM for 48 hours. It lowered PRMT5 and MEP50 levels and was associated with reduced cancer-cell behaviors in both cell lines. Forcing the cells to make extra PRMT5 or MEP50 weakened these effects of sulforaphane. In mice (10 tumors per group), sulforaphane given by mouth three times a week reduced tumor size compared with untreated controls (p less than 0.001). The authors concluded that sulforaphane may be a treatment agent for mesothelioma. They stated that the downstream proteins involved are not yet known.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study: experiments in cultured human mesothelioma cell lines plus a mouse tumor xenograft experiment
• Who was studied: Two human mesothelioma cell lines: Meso-1 (derived from peritoneal mesothelioma) and NCI-Meso-17 (derived from pleural mesothelioma). Also NSG mice injected with Meso-1 cells grown as spheroids: five mice with two tumors each, giving 10 tumors per treatment group.
• Exposure: No asbestos exposure was studied. The treatments tested were sulforaphane (SFN; 0 or 20 μM for 48 h in cells), siRNA knockdown of PRMT5 and/or MEP50, and the PRMT5 inhibitor GSK-3326595 (0 or 100 μM). In mice, SFN was given by oral gavage three times per week from week 9 to week 12. The methods give 25 μmoles/dose; the Figure 5 legend gives 20 μmoles/dose.
• Main results:
  • In Meso-1 cells, loss of PRMT5, or of PRMT5 and MEP50 together, was associated with reduced cell proliferation, spheroid formation, invasion and migration.
  • In Meso-1 cells, MEP50 knockdown alone reduced spheroid formation and invasion but was less effective on proliferation and migration.
  • In Meso-1 cells, the PRMT5 inhibitor GSK-3326595 reduced H4R3me2s formation and cell proliferation.
  • In Meso-1 cells, SFN reduced PRMT5 and MEP50 levels, and this was associated with reduced H4R3me2s formation.
  • In NCI-Meso-17 (pleural) cells, SFN reduced PRMT5/MEP50 and H4R3me2s formation, and this was associated with reduced invasion and migration.
  • Forced overexpression of PRMT5 or MEP50 counteracted SFN's suppression of spheroid formation, invasion and migration. The article reports a similar pattern in NCI-Meso-17 cells.
  • The proteasome inhibitor lactacystin did not reverse SFN's reduction of PRMT5 or MEP50. SFN reduced PRMT5 and MEP50 mRNA in both cell lines.
  • In mouse xenografts (n = 10 tumors, 2 tumors per mouse), SFN significantly reduced tumor size compared with control (p less than 0.001). This was associated with reduced PRMT5 and MEP50 mRNA and protein and reduced H4R3me2s.
• The authors' conclusion: The authors concluded that the PRMT5/MEP50 complex is required for optimal mesothelioma cell tumor formation, that SFN interferes with PRMT5/MEP50 function to reduce tumor formation, and that SFN may be a treatment agent for mesothelioma.
• Limitations the authors state:
  • The authors do not know which downstream proteins PRMT5/MEP50 act on to maintain the aggressive cancer phenotype.
  • It is not yet determined whether the mRNA loss after SFN is due to reduced transcription or enhanced mRNA degradation.
  • MEP50 was only partially reduced by knockdown, which the authors use to explain its weaker effects.
  • The increase in MEP50 after forced expression was less obvious than the increase in PRMT5.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Surgical Resection, Chemotherapy.

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