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

Authors :
Albert Agustinus
Mercedes Duran
Michael H. Goldbaum
David H. Abramson
Paul S. Mischel
Ashley M. Laughney
Jasmine H. Francis
Alexander N. Shoushtari
Mathieu F. Bakhoum
Melody Di Bona
Ethan M. Earlie
Samuel F. Bakhoum
Elsa Molina
Ignas Masilionis
Source :
Nature communications, vol 12, iss 1, Nature Communications, Vol 12, Iss 1, Pp 1-16 (2021), Nature Communications
Publication Year :
2021
Publisher :
eScholarship, University of California, 2021.

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.<br />The molecular underpinnings driving uveal melanoma (UM) progression are unknown. Here the authors show that loss of Polycomb Repressive Complex 1 triggers chromosomal instability, which promotes inflammatory signaling and migration in UM.

Details

Database :
OpenAIRE
Journal :
Nature communications, vol 12, iss 1, Nature Communications, Vol 12, Iss 1, Pp 1-16 (2021), Nature Communications
Accession number :
edsair.doi.dedup.....0c02d8097512dfd8970de2673fbbcc19