eLife Sciences: Loss of MGA repression mediated by an atypical polycomb complex promotes tumor progression and invasiveness (Shiio Lab)

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E Life Sciences

 

 

  1. Haritha Mathsyaraja 
  2. Jonathen Catchpole 
  3. Brian Freie 
  4. Emily Eastwood 
  5. Ekaterina Babaeva 
  6. Michael Geuenich 
  7. Pei Feng Cheng 
  8. Jessica Ayers 
  9. Ming Yu 
  10. Nan Wu 
  11. Sitapriya Moorthi 
  12. Kumud R Poudel 
  13. Amanda Koehne 
  14. William Grady 
  15. A McGarry Houghton 
  16. Alice H Berger 
  17. Yuzuru Shiio 
  18. David MacPherson  
  19. Robert N Eisenman

Abstract

MGA, a transcription factor and member of the MYC network, is mutated or deleted in a broad spectrum of malignancies. As a critical test of a tumor-suppressive role, we inactivated Mga in two mouse models of non-small cell lung cancer using a CRISPR-based approach. MGA loss significantly accelerated tumor growth in both models and led to de-repression of non-canonical Polycomb ncPRC1.6 targets, including genes involved in metastasis and meiosis. Moreover, MGA deletion in human lung adenocarcinoma lines augmented invasive capabilities. We further show that MGA-MAX, E2F6, and L3MBTL2 co-occupy thousands of promoters and that MGA stabilizes these ncPRC1.6 subunits. Lastly, we report that MGA loss also induces a pro-growth effect in human colon organoids. Our studies establish MGA as a bona fide tumor suppressor in vivo and suggest a tumor-suppressive mechanism in adenocarcinomas resulting from widespread transcriptional attenuation of MYC and E2F target genes mediated by MGA-MAX associated with a non-canonical Polycomb complex.

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Article Categories: Research Paper