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.

Therapeutical interference with the epigenetic landscape of germ cell tumors: a comparative drug study and new mechanistical insights

“…Regarding H2AK119ub after PRT4165 treatment , Ismail et al [ 50 ] observed diminished H2AK119ub within one hour of treatment. Even though similar observations have been found in another study using 92.1 uveal melanoma cells [ 59 ], reduced H2AK119ub levels could not be seen in MP38 cells, which displayed low basal activity of PRC1. Additionally, Desai et al observed a decrease in H2AK119ub upon treatment with PRT4165 for up to 36 h in undifferentiated KIND-1 (embryonic stem) cells, which displayed high RING1 protein levels, while BMI1 protein levels were rather low [ 60 ].…”

Recent advances in understanding the role of HES6 in cancers

“…MRK003, a NOTCH signaling inhibitor, reduced the viability and migration induced by mutant GNAQ 52 . Recently, single-cell RNA-seq analysis of freshly enucleated primary uveal melanomas revealed intratumor heterogeneity, which is considered a source of metastatic dissemination and therapy resistance in cancers 53 - 55 . Interestingly, an invasive cell state driven, at least in part, by HES6 was identified 55 , 56 .…”

Uveal Melanoma Metastasis

“…The dependency of BAP1 mutated UM on the Enhancer Of Zeste 2 Polycomb Repressive Complex 2 Subunit (EZH2) and hence the possibility to treat UM with EZH2 inhibitors has been controversially discussed [ 73 , 74 ]. Recent evidence obtained by single cell transcriptomics invokes the Polycomb Repressive Complex 1 (PRC1) and the associated ubiquitination state of lysine residue 119 in histone H2a as a major driver of UM progression [ 75 ]. Histone H2a is ubiquitinated by PCR1 and deubiquitinated by BAP1 [ 75 ].…”

“…Recent evidence obtained by single cell transcriptomics invokes the Polycomb Repressive Complex 1 (PRC1) and the associated ubiquitination state of lysine residue 119 in histone H2a as a major driver of UM progression [ 75 ]. Histone H2a is ubiquitinated by PCR1 and deubiquitinated by BAP1 [ 75 ]. A more complex genomic substructure of UM also emerges from another study based on single cell transcriptomics [ 28 ].…”