Interruption of aberrant chromatin looping is required for regenerating RB1 function and suppressing tumorigenesis

Abstract

RB transcriptional corepressor 1 (RB1) is a critical regulatory gene in physiological and pathological processes. Genetic mutation is considered to be the main cause of RB1 inactivation. However, accumulating evidence has shown that not all RB1 dysfunction is triggered by gene mutations, and the additional mechanism underlying RB1 dysfunction remains unclear. Here, we firstly reveal that a CCCTC binding factor (CTCF) mediated intrachromosomal looping served as a regulatory inducer to inactivate RB1. Once the core genomic fragment was deleted by Clustered Regularly Interspaced Short Palindromic Repeats/Cas9 (CRISPR/Cas9), this intrachromosomal looping was disrupted. After the open of chromatin, Enhancer of Zeste Homolog 2 (EZH2) was released and decreased the level of Tri-Methyl-Histone H3 Lys27 (H3K27me3) at the RB1 promoter, which substantially restored the expression of RB protein (pRB) and inhibited tumorigenesis. In addition, targeted correction of abnormal RB1 looping using the small-molecule compound GSK503 efficiently restored RB1 transcription and suppressed tumorigenesis. Our study reveals an alternative transcriptional mechanism underlying RB1 dysfunction independent of gene mutation, and advancing the discovery of potential therapeutic chemicals based on aberrant chromatin looping.

Study on the Effect of EZH2 Inhibitor Combined with TIGIT Monoclonal Antibody against Multiple Myeloma Cells

“…Another study using the EZH2 inhibitors EPZ005687 and UNC1999 in MM cell lines and patient samples confirmed that EZH2 inhibitors upregulate cell cycle control genes and reduce MM cell viability, leading to cell cycle arrest and apoptosis [18]. In addition, the EZH2 inhibitor GSK503 was proven to be effective in restoring RB transcriptional corepressor 1 transcription and suppressing tumorigenesis [23]. GSK503 inhibits the methyltransferase activity of wildtype and mutant EZH2 with high selectivity [24].…”