HP1γ promotes the progression of colorectal cancer through interaction with RBPJ of the Notch signaling pathway.

Abstract

Epigenetic dysregulation plays a pivotal role in cancer progression. Unlike HP1α and HP1β, which localize primarily to heterochromatin, HP1γ predominantly occupies euchromatin, suggesting a direct role in transcriptional regulation. Here, we identify HP1γ as a high-risk oncogene in colorectal cancer (CRC). Genome-wide analysis and disease-free survival (DFS) correlation studies revealed that high expression of HP1γ is associated with poor DFS in CRC patients, and we confirmed HP1γ upregulation in colon adenocarcinoma (COAD), the predominant CRC subtype. Functional assays demonstrated that HP1γ overexpression enhances tumor cell proliferation, migration, and colony formation in vitro, while siRNA-mediated knockdown suppressed these phenotypes. In vivo studies showed that HP1γ drives tumor growth, increasing both volume and weight in xenograft models. Mechanistically, HP1γ, via its chromo shadow domain (CSD), physically interacts with the beta-transducin repeat domain (BTD) of recombination signal binding protein for immunoglobulin kappa J region (RBPJ), the transcriptional factor of the Notch pathway. Intriguingly, RBPJ upregulation counteracts HP1γ-induced hyperproliferation, implicating HP1γ as a critical modulator of Notch signaling. Our findings establish HP1γ as a promoter of CRC progression through suppression of Notch pathway components, highlighting its potential as a diagnostic marker or therapeutic target in CRC.