The clinical value of HDAC2 and the p53-dependent signalling pathway in colorectal cancer

Colorectal cancer (CRC) is a leading cause of international morbidity and the second highest cause of cancer-related mortality. Incidence risks associated with CRC may be both environmental and behavioral, while disease complexity is characterized by genetic and epigenetic alterations. The up-regulation of the epigenetic regulator HDAC2 is one of most premature events in CRC carcinogenesis, while CRC progression is regulated by a series of mutations and chromosomal deletions of key oncogenes or tumor suppressor genes such as p53. One of the primary obstacles in accurately diagnosing CRC is the presence of mutations in the p53 gene, which disrupts the DNA mismatch repair pathway. Microsatellite instability (MSI) is a distinctive characteristic of CRC, and mutations in the DNA mismatch repair pathway are frequently observed. In 20% of cases, MSI in CRC is caused by the inactivation of one allele of a mismatch repair (MMR) gene by a germline mutation and subsequent somatic inactivation of the second allele. The remaining 80% of cases of sporadic tumours involve the somatic inactivation of both alleles of MLH1 gene, which is involved in DNA MMR by hypermethylation modifications (Lynch syndrome) or hereditary nonpolyposis colon cancer. Understanding the interaction between HDAC2 and p53 could potentially aid in identifying high-risk inherited colon cancer groups prone to developing CRC. HDAC2, a class I deacetylase, plays a critical role in regulating gene expression and chromatin structure. Research has demonstrated that CRC exhibits elevated levels of HDAC2, leading to enhanced cancer cell proliferation and metastasis. The regulation of the tumor suppressor p53 is influenced by HDAC2 through deacetylation, and HDAC2 also plays a role in maintaining genomic stability. HDAC inhibitors (HDACi) impact the enzymatic activity of HDAC2, indicating that this protein has a physiological function in cell proliferation, survival, and differentiation. HDACi treatment affects both mutant and wild-type p53 forms in CRC, although the exact mechanism is still unclear. Therefore the use of selective HDAC2 inhibitors could represent a versatile therapeutic strategy for CRC. The aim of this study is to identify HDAC2/p53 signatures that can enhance our understanding of CRC biology and to uncover potential targets for therapeutic interventions.