CC is the fourth most frequently diagnosed gynecological tumor, characterized by its high incidence and mortality rate (2). CC exhibits notable variations in both molecular and histological characteristics. Despite advancements in surgical procedures and integrated therapies, the prognosis for advanced or recurrent CC remains unfavorable. This emphasizes the immediate necessity to identify biological and therapeutic targets to improve the prognosis of CC. Histone acetylation plays a pivotal role in cancer initiation and progression, with many small molecule drugs currently under clinical investigation (18). Exploring its relationship with CC may aid in the development of innovative approaches for its management. This study comprehensively analyzed histone acetylation in CC development and constructed a prognostic model based on histone acetylation genes.
This study focused on 36 histone acetylation regulated genes as determined by the published literature (16). The expression of acetylated genes differed significantly between CC tissues and normal cervical tissues. Using bioinformatics and statistical tools, we evaluated the prognostic accuracy of these genes and selected KAT2B, HDAC5, and HDAC10 to construct prognostic models and calculate risk scores. These three core genes expression in CC was inferior to normal cervical tissues, and decreased expression of these three core genes had worse prognosis. Clinical samples confirmed reduced levels of HDAC5 and HDAC10 in CC tissues, suggesting their potential as diagnostic biomarkers.
Histone acetylation is a dynamic and reversible process regulated by HATs and HDACs. HATs enhance gene expression by altering the spatial organization of nucleosomes, leading to chromatin relaxation and increased gene transcription and replication.Conversely. HDACs enzymatically eliminate acetyl groups and bind to compact chromatin formations, therefore repressing transcription (19). Hence, the alteration of histones through acetylation is an essential epigenetic aspect in the biology of cancer (20). Currently, the specific function of HDAC proteins in cancer is not fully elucidated. Recent studies have shown that overexpression of numerous members of the HDAC family causes epigenetic silencing of tumor suppressor genes, which is a key step in carcinogenesis. Class I HDACs facilitate the regulation of the cell cycle, cell differentiation, and tissue development (21). HDAC6, one of Class II HDACs, can influence cell migration and other key biological processes (22). Therefore, HDAC inhibitors have been identified as supplementary therapeutic drugs for various types of human malignancies (23). On the other hand, HDACs have the potential to restrict tumor growth in certain cases. For example, data from the TCGA dataset revealed that deep deletions in HDAC10 were implicated in 5–10% of ovarian cancers. Furthermore, there is a correlation between low mRNA expression and susceptibility to platinum-based treatments (24). In this study, HDAC5 and HDAC10, both class II HDACs, exhibited lower expression in CC tissues, consistent with previous studies (25, 26). The possible mechanism involved the decrease in expression of HDAC10, which prevented the migration of CC cells and tumorigenesis by suppressing miR-223 expression through histone deacetylation (25). Additionally, it suppressed metastasis via inhibiting the expression of matrix metalloproteinase (MMP) 2 and 9 (27). Depletion of HDAC5 resulted in an elevation in acetylation of histone H3 lysine 27 (H3K27-ac) and bypassed the inhibitory effect of RB on cell-cycle-related pro-oncogenic genes (28).
An increasing number of researches suggested that components of tumor microenvironment (TME) played crucial roles in the development of cancer (29, 30). Epigenetics, particularly histone acetylation, not only regulates gene expression in tumor cells but also modulates TME components (31). To better understand the immune response against CC, we investigated the correlation between histone acetylation modifications and TME cell infiltration. Our prognostic model highlighted a significant association between histone acetylation and the TME, pointing to key immune checkpoints such as anti-programmed cell death 1 (PD-1) and TIM-3. Consistent with previous studies, these checkpoints were crucial in restoring anti-tumor immunity, which allowed for the reversal of immune evasion and the promotion of tumor cell death (32, 33). Furthermore, our findings suggested immune-related functions were negatively correlated with our risk scores, indicating immune evasion susceptibility in high-risk groups. Further exploration into the therapeutic implications of histone acetylation identified potential sensitivities to chemotherapeutic drugs like vemurafenib and dabrafenib in CC. This discovery could play a significant role in advancing new treatments for CC and in preventing drug resistance.
Despite these observations, our study has limitations. Firstly, we should expand our clinical sample size to validate the expression of these key genes in cervical cancer. Additionally, the mechanistic functions of crucial genes and prognostic factors need further confirmation through in vivo studies and controlled laboratory experiments (in vitro).