Loss of polycomb repressive complex 1 activity and chromosomal instability drive uveal melanoma progression. Academic Article uri icon

Overview

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.

publication date

  • September 13, 2021

Research

keywords

  • Chromosomal Instability
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Melanoma
  • Polycomb Repressive Complex 1
  • Uveal Neoplasms

Identity

PubMed Central ID

  • PMC8438051

Scopus Document Identifier

  • 85114879709

Digital Object Identifier (DOI)

  • 10.1126/scisignal.2004088

PubMed ID

  • 34518527

Additional Document Info

volume

  • 12

issue

  • 1