Comprehensive Analysis of HDAC Family Identifies HDAC1 as a Prognostic and Immune Infiltration Indicator and HDAC1-Related Signature for Prognosis in Glioma

Abstract

Background: The histone deacetylase (HDAC) family limited accessibility to chromatin containing tumor suppressor genes by removing acetyl groups, which was deemed a path for tumorigenesis. Considering glioma remained one of the most common brain cancers with a dichotomy prognosis and limited therapy responses, HDAC inhibitors were an area of intensive research. However, the expression profiles and prognostic value of the HDACs required more elucidation.Methods: Multiple biomedical databases were incorporated, including ONCOMINE, GEPIA, TCGA, CGGA, GEO, TIMER, cBioPortal, and Metascape, to study expression profiles, prognostic value, immune infiltration, mutation status, and enrichment of HDACs in glioma. STRING and GeneMANIA databases were used to identify HDAC1-related molecules. LASSO regression, Cox regression, Kaplan-Meier plot, and receiver operating characteristic (ROC) analyses were performed for HDAC1-related signature construction and validation.Results:HDAC1 was significantly overexpressed in glioma, while HDAC11 was downregulated in glioblastoma. Except for HDAC 6/9/10, the HDAC family expression was significantly associated with glioma grade. Most of the HDAC family also correlated with glioma genetic mutations. Higher HDAC1 expression level predicted more dismal overall survival (OS) (p < 0.0001) and disease-free survival (DFS) (p < 0.0001), but a higher level of HDAC11 held more favorable OS (p = 2.1e−14) and DFS (p = 4.8e−08). HDAC4 displayed the highest mutation ratio, at 2.6% of the family. The prognostic value of HDAC1 was validated with ROC achieving 0.70, 0.77, 0.75, and 0.80 as separability for 1-, 3-, 5-, and 10-years OS predictions in glioma, respectively. Moreover, HDAC1 expression positively correlated with neutrophil (r = 0.60, p = 2.88e-47) and CD4+ T cell infiltration (r = 0.52, p = 3.96e-35) in lower-grade glioma. The final HDAC1-related signature comprised of FKBP3, HDAC1 (Hazard Ratio:1.49, 95%Confidence Interval:1.20–1.86), PHF21A, RUNX1T1, and RBL1, and was verified by survival analysis (p < 0.0001) and ROC with 0.80, 0.84, 0.83, and 0.88 as separability for 1-, 3-, 5-, and 10-years OS predictions, respectively. The signature was enriched in chromatin binding.Conclusion: HDAC family was of clinical significance for glioma. Most of the HDAC family significantly correlated with the glioma grade, IDH1 mutation, and 1p/19q codeletion. HDAC1 was both a prognostic and immune infiltration indicator and a central component of the HDAC1-related signature for precise prognosis prediction in glioma.

PODNL1 Methylation Serves as a Prognostic Biomarker and Associates with Immune Cell Infiltration and Immune Checkpoint Blockade Response in Lower-Grade Glioma

“…Increased immune cell infiltration levels are linked to heightened tumor aggressiveness in a range of cancers including breast cancer, kidney renal clear cell carcinoma, uveal melanoma, pancreatic cancer, and osteosarcoma [41][42][43][44][45][46][47][48]. In gliomas, including LGG, increased immune cell infiltration levels showed poor prognosis and more aggressive phenotypes [21,22,[49][50][51][52][53][54][55][56][57]. Thus, we report that low PODNL1 methylation, specifically of CpG sites cg07425555, cg26969888, cg18547299, and cg24354933, may be a key factor in the modulation of immune infiltrates in the LGG tumor microenvironment, affecting its aggressiveness and prognosis.…”

Construction and validation of an angiogenesis-related gene expression signature associated with clinical outcome and tumor immune microenvironment in glioma

“…Furthermore, we compared the prognostic predictive abilities of 20 different risk signatures of gliomas in TCGA from published articles, including inflammatory response-related gene (IRRG) signature ( Yan et al, 2022 ), DNA damage and repair-related gene (DDRRG) signature ( Li et al, 2022c ), CXCR members signature ( He et al, 2022 ), pyroptosis-related gene signature ( Zhang M. et al, 2021b ; Chao et al, 2022 ; Yang et al, 2022 ; Zhang et al, 2022 ), ECM-related gene (ECMRG) signature ( Li et al, 2022b ), tripartite motif (TRIM) family gene signature ( Xiao et al, 2022 ), antigen presentation machinery (APM) signature ( Chen et al, 2022 ), natural killer cell-related gene (NKRG) signature ( Li C. et al, 2022a ), IL-4-related gene (IL4RG) signature ( Qi et al, 2022 ), hypoxia-related gene (HRG) signature ( Gao et al, 2021 ), S100 family-based signature ( Hu et al, 2021 ), TIME signature ( Zhang C. et al, 2021a ), focal adhesion-related gene (FARG) signature ( Li et al, 2021 ), m6A RNA methylation regulator signature ( Cong et al, 2021 ), HDAC1-related signature ( Fan et al, 2021 ), RNA-binding protein (RBP)-based signature ( Chen et al, 2021a ) and ferroptosis-related gene (FRG) signature ( Chen et al, 2021b ). The results of univariate and multivariate Cox analyses showed that our ARG signature had independent predictive ability ( p < 0.001, Table 1 ).…”

Comprehensive analysis of histone deacetylases genes in the prognosis and immune infiltration of glioma patients

“…Previous studies have indicated that HDAC1 is overexpressed in diverse human malignancies, such as prostate cancer, breast cancer, liver cancer, and lung cancer [ 18 – 21 ]. HDAC1 is also highly expressed in glioma tissue, and high expression of glioma is associated with glioma cell proliferation, migration, invasion, angiogenesis, and a poor prognosis [ 22 ]. In addition, has been suggested that increased activation of HDAC1/2/6 and Sp1 underlies therapeutic resistance and tumor growth in glioblastoma [ 23 ].…”