As an indispensable part of precision medicine in cancer, biomarkers are important for predicting cancer prognosis and treatment effects15,16. Various prognostic biomarkers and prognostic markers have been identified and established in previous research17,18.
HDACs are indispensable transcriptional repressors involved in many physiological and pathological processes. Among these proteins, the class IIa HDAC subfamily, which includes HDAC4, HDAC5, HDAC7, and HDAC9, shares the specific characteristics with all other HDACs, such as interaction with transcription factors and tissue specificity5. Among them, HDAC7 seems to act as a lymphoid-specific transcription inhibitor of various HDACs19. Here, we found that HDAC7 can be used as a biomarker for better prognosis and longer survival in patients with DLBCL.
In this study, through TCGA data mining, we revealed the relationship between HDAC7 expression and survival of patients with DLBCL. Our results showed that HDAC7 expression was higher in DLBCL tumors than in normal lymph node tissues. However, in an internal comparison between patients with tumors, we found that HDAC7 expression was significantly higher in patients with stage I and II disease than in those with stage III and IV disease. Our IHC staining results, which validated the protein expression of HDAC7, were consistent with the above analysis. We found that elevated HDAC7 expression was associated with better OS and PFS with moderate diagnostic accuracy. Moreover, logistic regression analysis indicated that HDAC7 was significantly associated with DSS, PFS, and better primary therapy outcomes (complete and partial responses). Univariate/multivariate Cox hazard regression analysis also indicated that HDAC7 could act as an independent prognostic factor for DLBCL. In conclusion, these results suggest that HDAC7 may act as a prognostic predictor of survival in patients with DLBCL.
As predictive tools, nomograms have been widely used to assist in clinical decision-making20,21. In this study, we created a nomogram using HDAC7 and four clinical parameters (age, grade, clinical stage, main treatment outcome, and HDAC7 expression) to predict the OS of patients with DLBCL. The C-index; 1-, 3-, and 5-year AUCs; and calibration curves indicated that this nomogram had a moderate prediction accuracy and satisfactory performance. Overall, we successfully established an HDAC7-based nomogram that is anticipated to guide the prognosis of patients with DLBCL.
To identify HDAC7-related signaling pathways and immunity, we further explored the potential relationships between HDAC7 and immunity, focusing on three aspects: tumor immune infiltration, immune cell pathways, and immune checkpoint molecules. As reported in previous studies, the tumor microenvironment and tumor immune infiltration are associated with DLBCL prognosis and response to immunotherapy, and various genes are significantly associated with immune cell pathways and checkpoint molecules22,23. According to a previous study, naïve B cells, gamma delta T cells, and resting NK cells are the three most affected immune cells that influence several steps in the DLBCL immunity cycle24. In our research, regarding tumor immune infiltration, high levels of HDAC7 were significantly associated with downregulated infiltration of dendritic, cytotoxic, aDC, and T cells. Co-expression analysis showed that HDAC7 was markedly related to B2M, ACTB, CD79B, BTG1, TET2, and POU2F2 in DLBCL. Overall, our study showed that HDAC7 may be closely related to immunity in DLBCL.
The relationship between gene expression and tumor metastasis and development has attracted attention. Over the years, with the help of single gene assessment methods, it has been found that gene mutation or expression cannot be ignored in the pathogenesis of DLBCL25. Many cellular processes and pathways are involved in gene mutations in DLBCL, including histone modification (methylation and acetylation), cell growth, proliferation, metabolism, differentiation, apoptosis, survival, homing/migration, response to DNA damage, B-cell receptor signaling, Toll-like receptor signaling, angiogenesis, and immunoregulation26–28. Through gene expression, we can understand the pathogenesis of the disease and, at the same time, use this as a potential target of prognostic value. The proper development of B lymphocytes depends on a genetic program unique to each cell stage that is based on appropriate transcriptional control. When these specific transcriptional controls are relaxed, B cell maturation is impeded, which is likely to lead to the development of hematological malignancies, such as leukemia and lymphoma. Moreover, HDAC7 expression plays an important role in inducing apoptosis and inhibiting the oncogenic potential of the cell lines tested in vitro and in vivo. In contrast, genome-wide transcriptome profiling showed that ectopically expressed HDAC7 induces the expression of apoptotic genes and leads to the downregulation of key oncogenes, such as c-Myc29. DLBCL patients with MYC translocations at the immunoglobulin gene locus have a worse prognosis than those with a non-immunoglobulin gene partner30. In some studies, HDAC7 expression was lower in samples from patients with B lymphocytes with a high Myc expression29. The results from our study agree with this assumption and show that high expression of HDAC7 is associated with a lower degree of immune infiltration, which may play a role in inhibiting oncogenic potential. Further studies are required to confirm this association.
Our analysis shares some common limitations with similar studies. First, owing to the retrospective nature of the study, clinical information from TCGA was limited, and some important data could not be obtained. Second, our IHC staining verification results indicated that HDAC7 protein displayed relatively low expression in DLBCL tumors compared to the findings of previous studies. This was likely due to the limited number of clinical samples. Therefore, subsequent experiments should be performed using more samples to verify this expression. Moreover, we verified the potential mechanisms of HDAC7 in DLBCL at both cellular and molecular levels. Notwithstanding these limitations, our study had several strengths. To our knowledge, this is the first study to explore the role of HDAC7 in DLBCL. In addition, multiple elements were analyzed for HDAC7 in DLBCL, including mutation features, nomogram, PPI, tumor immune infiltration, immune cell pathways, and checkpoint molecules.
Recent advances in understanding the molecular discoveries in DLBCL can help in the development of novel and highly effective therapies for patients with DLBCL. Thus, we are fulfilling the potential of precision medicine. It is our hope that we can use the knowledge gained to develop innovative therapeutics1.