Deficiency of the Polycomb Protein RYBP and TET Methylcytosine Oxidases Promotes Extensive CpG Island Hypermethylation and Malignant Transformation

Abstract

Hypermethylation of CpG islands is a common feature of cancer cells and predominantly affects Polycomb-associated genomic regions. Elucidating the underlying mechanisms leading to DNA hypermethylation in human cancer could help identify chemoprevention strategies. Here, we evaluated the role of Polycomb complexes and 5-methylcytosine oxidases in protecting CpG islands from DNA methylation and observed that four genes coding for components of Polycomb repressive complex 1 (PRC1) are downregulated in tumors. Inactivation of RYBP, a key activator of variant PRC1 complexes, in combination with all three 5-methylcytosine oxidases (TET proteins) in nontumorigenic bronchial epithelial cells led to widespread hypermethylation of Polycomb-marked CpG islands affecting almost 4,000 target genes, which closely resembled the DNA hypermethylation landscape observed in human squamous cell lung tumors. The RYBP- and TET-deficient cells showed methylation-associated aberrant regulation of cancer-relevant pathways, including defects in the Hippo tumor suppressor network. Notably, the quadruple knockout cells acquired a transformed phenotype, including anchorage-independent growth and formation of squamous cell carcinomas in mice. This work provides a mechanism promoting hypermethylation of CpG islands and shows that such hypermethylation can lead to cell transformation. The breakdown of a two-pronged protection mechanism can be a route towards genome-wide hypermethylation of CpG islands in tumors.

Targeting iron–sulfur cluster assembly scaffold protein as a vulnerability in KRAS‐activated pancreatic ductal adenocarcinoma

“…Ren et al 2 revealed that activated KRAS enhances the DNA methylation by the control of ISCU‐promoted α‐KG catabolism and TET3 inhibition. The alterations in DNA 5mC methylation are associated with the development of diseases, especially malignant tumor 8 . Therefore, the increase of ISCU‐mediated DNA 5mC level may alter the expression of numerous genes.…”

Homeobox and Polycomb target gene methylation in human solid tumors

“…PRC2 targets also play a role in cancer onset and progression. These target genes have been shown to overlap with differentially methylated CpGs in several human cancers [12][13][14][15][16][17] .…”