Ezh2 promotes mammary tumor initiation through epigenetic regulation of the Wnt and mTORC1 signaling pathways

Abstract

The regulation of gene expression through histone posttranslational modifications plays a crucial role in breast cancer progression. However, the molecular mechanisms underlying the contribution of histone modification to tumor initiation remain unclear. To gain a deeper understanding of the role of the histone modifier Enhancer of Zeste homology 2 (Ezh2) in the early stages of mammary tumor progression, we employed an inducible mammary organoid system bearing conditional Ezh2 alleles that faithfully recapitulates key events of luminal B breast cancer initiation. We showed that the loss of Ezh2 severely impairs oncogene-induced organoid growth, with Ezh2-deficient organoids maintaining a polarized epithelial phenotype. Transcriptomic profiling showed that Ezh2-deficient mammary epithelial cells up-regulated the expression of negative regulators of Wnt signaling and down-regulated genes involved in mTORC1 (mechanistic target of rapamycin complex 1) signaling. We identified Sfrp1 , a Wnt signaling suppressor, as an Ezh2 target gene that is derepressed and expressed in Ezh2-deficient epithelium. Furthermore, an analysis of breast cancer data revealed that Sfrp1 expression was associated with favorable clinical outcomes in luminal B breast cancer patients. Finally, we confirmed that targeting Ezh2 impairs mTORC1 activity through an indirect mechanism that up-regulates the expression of the tumor suppressor Pten. These findings indicate that Ezh2 integrates the mTORC1 and Wnt signaling pathways during early mammary tumor progression, arguing that inhibiting Ezh2 or therapeutically targeting Ezh2-dependent programs could be beneficial for the treatment of early-stage luminal B breast cancer.

Unraveling malignant phenotype of peritumoral tissue: transcriptomic insights into early-stage breast cancer

“…Highlighting the top ten upregulated nodes of the PPI subnetwork that compares peritumoral and non-tumoral tissues, our results showed a high interaction between most of them involving cell cycle, inflammation, and proliferative phenotype processes. In addition to the main nodes mentioned, BUB1, CCND1, CDK1, and PCNA, other studies also show the importance of NOP58, EZH2 and PPPC1A in tumorigenesis [ 44 – 46 ]. All these genes are interconnected in a complex network that ensures the correct control of cell division and genomic stability, emphasizing CDK1, as master regulator [ 39 ].…”

EZH2 Inhibition Enhances PD‐L1 Protein Stability Through USP22‐Mediated Deubiquitination in Colorectal Cancer

“…The histone methyltransferase EZH2 is widely recognized as a tumor‐promoting regulatory molecule. [ 38 ] Despite the abnormal expression of EZH2 in tumors, EZH2 inhibitors are only effective in limited types of tumors, and clinical trials in most solid tumors appear unsatisfactory. The reason may be that EZH2 inhibitors also dynamically affect the tumor microenvironment, such as reprogramming the metabolic profile and/or weakening antitumor functions, such as producing an immunosuppressive effect by enhancing PD‐L1 expression.…”

Unraveling the relationship between histone methylation and nonalcoholic fatty liver disease

“…Like H3K9 methylation, hypermethylation of H3K27 also serves as a universal repressor in gene transcription. The accrual of H3K27me3, facilitated by the methyltransferase EZH2, inhibits the transcription of Wnt signaling antagonists, consequently activating Wnt/β-catenin protein signaling and fostering tumor aggressiveness[ 91 - 93 ]. On the contrary, the methylation of H4K20 induced by the methyltransferase KMT5A is involved in the activation of gene transcription, regulation of DNA replication, repair of DNA damage, and control of the cell cycle[ 94 , 95 ], ultimately resulting in a negative prognosis and adverse outcomes in HCC.…”