Development and Validation of a Prognostic Signature Based on the Lysine Crotonylation Regulators in Head and Neck Squamous Cell Carcinoma

Abstract

Background. Lysine crotonylation (Kcr) is a newly identified posttranslational modification type regulated by various enzymes and coenzymes, including lysine crotonyltransferase, lysine decrotonylase, and binding proteins. However, the role of Kcr regulators in head and neck squamous cell carcinoma (HNSCC) remains unknown. The aim of this study was to establish and validate a Kcr-related prognostic signature of HNSCC and to assess the clinical predictive value of this signature. Methods. The mRNA expression profiles and clinicopathological data from The Cancer Genome Atlas (TCGA) database were downloaded to explore the clinical significance and prognostic value of these regulators in HNSCC. The least absolute shrinkage and selection operator (LASSO) Cox regression model was used to generate the Kcr-related prognostic signature for HNSCC. Subsequently, the GSE65858 dataset from the Gene Expression Omnibus (GEO) database was used to validate the signature. The prognostic value of the signature was evaluated using the Kaplan-Meier survival, receiver operating characteristic (ROC) curve, and univariate and multivariate Cox regression analyses. Results. We established a nine-gene risk signature associated with the prognosis of HNSCC based on Kcr regulators. High-risk patients demonstrated significantly poorer overall survival (OS) than low-risk patients in the training (TCGA) and validation (GEO) datasets. Then, the time-dependent receiver operating characteristic (ROC) curve analysis showed that the nine-gene risk signature was more accurate for predicting the 5-year OS than other clinical parameters, including age, gender, T stage, N stage, and histologic grade in the TCGA and GEO datasets. Moreover, the Cox regression analysis showed that the constructed risk signature was an independent risk factor for HNSCC. Conclusion. Our study identified and validated a nine-gene signature for HNSCC based on Kcr regulators. These results might contribute to prognosis stratification and treatment escalation for HNSCC patients.

A glimpse into novel acylations and their emerging role in regulating cancer metastasis

“…Moreover, it was also reported that most Kcr regulators, including DPF2, KAT2B, and HDAC2–3, were significantly dysregulated in patients with head and neck squamous cell carcinoma (HNSCC); this observation positively correlated with lymph-node metastasis, T stage, and histologic grade [ 126 ]. Specifically, KAT2B decreased in the advanced compared with the early T stage ( p = 0.0016), disclosing the negative correlation between KAT2B and the T stage.…”

“…SUCLG2 is estimated to be a biomarker candidate that can effectively differentiate between follicular adenoma and carcinoma with 75% sensitivity and 80% specificity, depending on a specific cutoff score extrapolated from the intensity and percentage of immunohistochemistry (IHC) staining [ 125 ]. Based on Kcr regulators, a nine-gene signature, including DPF2, HDAC2, and HDAC3, was established and validated as an independent factor for prognosis in patients with HNSCC; this could effectively distinguish patients into low- and high-risk groups depending on the difference in OS using the GEO-HNSCC dataset ( p = 0.023) [ 126 ]. Univariate analysis of training cohorts revealed that the risk characteristics obtained from the nine-gene regulators were significantly associated with OS ( p < 0.001, HR 4.175, 95% CI 2.573–6.776); the nine-gene risk assessment from the multivariate analysis further verified their potential as independent prognostic factors ( p < 0.001, HR 3.500, 95% CI 2.178–5.625) [ 126 ].…”

“…Based on Kcr regulators, a nine-gene signature, including DPF2, HDAC2, and HDAC3, was established and validated as an independent factor for prognosis in patients with HNSCC; this could effectively distinguish patients into low- and high-risk groups depending on the difference in OS using the GEO-HNSCC dataset ( p = 0.023) [ 126 ]. Univariate analysis of training cohorts revealed that the risk characteristics obtained from the nine-gene regulators were significantly associated with OS ( p < 0.001, HR 4.175, 95% CI 2.573–6.776); the nine-gene risk assessment from the multivariate analysis further verified their potential as independent prognostic factors ( p < 0.001, HR 3.500, 95% CI 2.178–5.625) [ 126 ]. Additionally, the TNM stage of multiple types of cancers directly correlated with novel acylation; e.g., liver cancer tumor tissues show higher succinylation levels than adjacent tissues ( p < 0.001), and according to the univariate and multivariate analyses, the OS closely correlates with the Ksuc intensity (IHC score; univariate analysis: p = 0.0073, HR 1.2, 95% CI 1.1–1.4; multivariate analysis: p = 0.00023, HR 1.29, 95% CI 1.13–1.48) [ 144 ].…”

Histone modifications in head and neck squamous cell carcinoma

“…This modification is catalyzed by a family of enzymes called histone crotonyltransferases (KAT5/8), which use crotonyl-CoA as a cosubstrate. Histone crotonylation can activate or repress the transcription of specific genes in HNSCC by altering chromatin structure, thereby influencing disease progression ( 38 ). Through sequencing and enrichment analysis, it has been found that histone malonylation of HSP90AB1 mediates the onset and progression of oral squamous cell carcinoma ( 39 ).…”