Loss of polycomb repressive complex 1 activity and chromosomal instability drive uveal melanoma progression Journal Article


Authors: Bakhoum, M. F.; Francis, J. H.; Agustinus, A.; Earlie, E. M.; Di Bona, M.; Abramson, D. H.; Duran, M.; Masilionis, I.; Molina, E.; Shoushtari, A. N.; Goldbaum, M. H.; Mischel, P. S.; Bakhoum, S. F.; Laughney, A. M.
Article Title: Loss of polycomb repressive complex 1 activity and chromosomal instability drive uveal melanoma progression
Abstract: Chromosomal instability (CIN) and epigenetic alterations have been implicated in tumor progression and metastasis; yet how these two hallmarks of cancer are related remains poorly understood. By integrating genetic, epigenetic, and functional analyses at the single cell level, we show that progression of uveal melanoma (UM), the most common intraocular primary cancer in adults, is driven by loss of Polycomb Repressive Complex 1 (PRC1) in a subpopulation of tumor cells. This leads to transcriptional de-repression of PRC1-target genes and mitotic chromosome segregation errors. Ensuing CIN leads to the formation of rupture-prone micronuclei, exposing genomic double-stranded DNA (dsDNA) to the cytosol. This provokes tumor cell-intrinsic inflammatory signaling, mediated by aberrant activation of the cGAS-STING pathway. PRC1 inhibition promotes nuclear enlargement, induces a transcriptional response that is associated with significantly worse patient survival and clinical outcomes, and enhances migration that is rescued upon pharmacologic inhibition of CIN or STING. Thus, deregulation of PRC1 can promote tumor progression by inducing CIN and represents an opportunity for early therapeutic intervention. © 2021, The Author(s).
Journal Title: Nature Communications
Volume: 12
ISSN: 2041-1723
Publisher: Nature Publishing Group  
Date Published: 2021-09-13
Start Page: 5402
Language: English
DOI: 10.1038/s41467-021-25529-z
PROVIDER: scopus
PMCID: PMC8438051
PUBMED: 34518527
DOI/URL:
Notes: Article -- Export Date: 1 October 2021 -- Source: Scopus
Altmetric
Citation Impact
MSK Authors
  1. Jasmine Helen Francis
    163 Francis
  2. David H Abramson
    316 Abramson
  3. Samuel F Bakhoum
    40 Bakhoum
  4. Mercedes A Duran
    4 Duran