Mechanisms of Polycomb group protein function in cancer

Abstract

Cancer arises from a multitude of disorders resulting in loss of differentiation and a stem cell-like phenotype characterized by uncontrolled growth. Polycomb Group (PcG) proteins are members of multiprotein complexes that are highly conserved throughout evolution. Historically, they have been described as essential for maintaining epigenetic cellular memory by locking homeotic genes in a transcriptionally repressed state. What was initially thought to be a function restricted to a few target genes, subsequently turned out to be of much broader relevance, since the main role of PcG complexes is to ensure a dynamically choregraphed spatio-temporal regulation of their numerous target genes during development. Their ability to modify chromatin landscapes and refine the expression of master genes controlling major switches in cellular decisions under physiological conditions is often misregulated in tumors. Surprisingly, their functional implication in the initiation and progression of cancer may be either dependent on Polycomb complexes, or specific for a subunit that acts independently of other PcG members. In this review, we describe how misregulated Polycomb proteins play a pleiotropic role in cancer by altering a broad spectrum of biological processes such as the proliferation-differentiation balance, metabolism and the immune response, all of which are crucial in tumor progression. We also illustrate how interfering with PcG functions can provide a powerful strategy to counter tumor progression.

Transcriptome Architecture of Osteoblastic Cells Infected With Staphylococcus aureus Reveals Strong Inflammatory Responses and Signatures of Metabolic and Epigenetic Dysregulation

“…This inhibition of chromatin repression mechanisms may play an important role in the concomitant and potent activation of genes associated with inflammation and immunity by overcoming transcriptional blocks at target genes. These epigenetic mechanisms include components of macromolecular chromatin-repressive complexes, such as NurD ( Xue et al., 1998 , Denslow et al., 2007 ), Polycomb-repressive complex PRC1 ( Parreno et al., 2022 ), and the recently described BAHD1 complex ( Bierne H. et al., 2011 ; Lakisic et al., 2016 ). Interestingly, BAHD1 and NurD are known to be controlled by the pathogens Listeria monocytogenes and Mycobacterium tuberculosis , ( Lebreton et al., 2012 ; Olias et al., 2016 ), resulting in deregulation of interferon responses ( Lebreton et al., 2011 ).…”

De Novo Polycomb Recruitment and Repressive Domain Formation

“…This evidence suggests that the sites where H3K27M and Ezhip stall the PRC2 complex may coincide with the de novo recruitment sites, although this is an unproven hypothesis. Hence, an example of how Polycomb dysregulation, particularly de novo recruitment, renders the development of certain disorders such as cancer [ 189 , 190 , 191 , 192 , 193 ]. Similarly, the Eed mutant protein found in the Weaver syndrome is deficient in spreading H3K27me3 [ 142 ], potentially explaining the genetic deregulation in the disease.…”

Polycomb Directed Cell Fate Decisions in Development and Cancer

“…PRC2 is subdivided into two types, depending on the interactions with the differentially expressed accessory subunits, PRC2.1 and PRC2.2, which influence the function of the complex and the chromatin recruitment [ 72 ] ( Figure 2 A). The PRC2.1 complex comprises three paralogous polycomb-like (PCL) proteins PCL1/2/3, also called PHF1, MTF2 and PHF19, as well as Elongin B/C and PRC2-associated protein (EPOP), or PRC2-associated LCOR isoform 1/2 (PALI1/2).…”

“…In addition, in mammals (represented in black), PRC2 recruitment occurs at CGIs, via transcription factors, lncRNAs, or an alternative recruitment pathway, in which non-canonical PRC1 (ncPRC1) complexes are recruited in a KDM2B-dependent manner, which deposits the H2AK119 ubiquitination mark recognized by the JARID2 and PCL1/2/3 subunits of PRC2.2 and PRC2.1, respectively. Figure modified from [ 72 ] and generated in .…”