Construction and verification of a histone deacetylases-related prognostic signature model for colon cancer

TL;DR

This study creates a model using histone deacetylases to predict colon cancer prognosis and treatment response.

Contribution

A novel HDAC-related prognostic model for COAD is developed and validated with clinical and genomic data.

Findings

HDAC-related features are independent prognostic factors for COAD patient survival.

Low-risk group patients show better prognosis and higher response to anti-PD-1 therapy.

BRD3 inhibition reduces cancer cell proliferation and migration while promoting apoptosis.

Abstract

Histone deacetylases (HDACs) contribute significantly to the initiation, progression, and prognosis of colorectal adenocarcinoma (COAD). Additionally, HDACs regulate the tumor microenvironment, immune escape, and tumor stem cells, and are closely linked to COAD prognosis. We developed a prognostic model for COAD that incorporates HDACs to evaluate their specific roles. The COAD dataset containing clinical and mutation data was collected using the TCGA and GEO databases to obtain genes associated with HDAC. LASSO analysis and univariate and multivariate Cox regression analysis were used to determine the presence of prognostic genes. Multivariate Cox analysis was also used to determine risk scores for HDAC-related features. Furthermore, genomic alterations, immune infiltration, and drug response were compared between high- and low-risk groups. Cellular experiments validated the potential regulatory role of BRD3 on COAD proliferation, migration, and apoptosis. The median risk scores, calculated based on the characteristics, demonstrated a more significant prognostic improvement in patients in the low-risk group. Furthermore, HDAC-related features were identified as important independent prognostic factors for patients with COAD. Additionally, genomic mutation status, immune infiltration, and function, as well as response to immunotherapy and chemotherapy, were found to be associated with risk scores. Subgroup analyses indicate that anti-PD-1 therapy may be beneficial for patients in the low-risk group. Additionally, a decrease in risk score was associated with a decrease in immune infiltration. Finally, HCT116 and HT29 cells exhibited inhibition of BRD3 gene proliferation and migration, as well as promotion of apoptosis. In patients with COAD, HDAC-related characteristics may be useful in predicting survival and selecting treatment.

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