PHF20L1 as a H3K27me2 reader coordinates with transcriptional repressors to promote breast tumorigenesis.

Abstract

TUDOR domain-containing proteins (TDRDs) are chiefly responsible for recognizing methyl-lysine/arginine residue. However, how TDRD dysregulation contributes to breast tumorigenesis is poorly understood. Here, we report that TUDOR domain-containing PHF20L1 as a H3K27me2 reader exerts transcriptional repression by recruiting polycomb repressive complex 2 (PRC2) and Mi-2/nucleosome remodeling and deacetylase (NuRD) complex, linking PRC2-mediated methylation and NuRD-mediated deacetylation of H3K27. Furthermore, PHF20L1 was found to serve as a potential MYC and hypoxia-driven oncogene, promoting glycolysis, proliferation, and metastasis of breast cancer cells by directly inhibiting tumor suppressors such as <i>HIC1</i>, <i>KISS1</i>, and <i>BRCA1</i>. PHF20L1 expression was also strongly correlated with higher histologic grades of breast cancer and markedly up-regulated in several cancers. Meanwhile, <i>Phf20l1</i> deletion not only induces growth retardation and mammary ductal outgrowth delay but also inhibits tumorigenesis in vivo. Our data indicate that PHF20L1 promotes tumorigenesis, supporting the pursuit of PHF20L1 as a target for cancer therapy.