Hypermethylated WASF2: tumor suppressive role in head and neck squamous cell carcinoma

Jianyun Zhang; Zhuang Ding; Long Chen; Haiyan Qin

doi:10.21037/tcr-22-1133

Hypermethylated WASF2: tumor suppressive role in head and neck squamous cell carcinoma

Transl Cancer Res. 2023 Jan 30;12(1):78-92. doi: 10.21037/tcr-22-1133. Epub 2022 Dec 31.

Authors

Jianyun Zhang^#¹, Zhuang Ding^#¹, Long Chen¹, Haiyan Qin²

Affiliations

¹ Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China.
² Department of Dental Implantology and Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China.

^# Contributed equally.

Abstract

Background: WASF2 regulates actin reorganization during cell migration. WASF2 has been identified as a regulator of the development of gastric cancer, breast cancer, and pancreatic cancer. But its regulatory mechanisms remain unknown. Also, its function was absent in head and neck squamous cell carcinoma (HNSCC). Consequently, we examined the effect of DNA methylation on aberrant WASF2 expression in HNSCC.

Methods: TNMplot, TIMER, GSEA pathway analysis, and the Kaplan-Meier Plotter database were used to analyze the expression, function, and prognostic value of WASF2, as well as the correlation between WASF2 and infiltrating immune cells in HNSCC or pan-cancer analysis. WASF2 promoter methylation levels and the correlation between WASF2 expression and WASF2 promoter methylation in HNSCC were evaluated using the DNMIVD database. The effect of DNA methylation inhibitor on WASF2 expression was demonstrated in the GEO database. Finally, the TISIDB database determined the relationships between WASF2 methylation, immune cell infiltration, and immune inhibitors.

Results: WASF2 was significantly downregulated in HNSCC tissues where WASF2 promoter methylation was elevated. According to the GEO database, treatment with a DNA methylation inhibitor notably restored the mRNA expression of WASF2. WASF2 expression was also a favorable indicator of human papilloma virus (HPV)-positive HNSCC. Its level of promoter methylation had detrimental effects on patient survival. In addition, patients with elevated levels of WASF2 demonstrated active G2/M regulation, TGF-β signaling, Kras signaling, fatty acid metabolism, and p53 pathways. WASF2 was positively associated with tumor-killing immune cells, while WASF2 methylation was positively related to immunosuppressive cells and immune-inhibitors.

Conclusions: Hypermethylated WASF2 acted as a tumor suppressor of HNSCC by regulating tumor formation and immune imbalance.

Keywords: WASF2; head and neck squamous cell carcinoma (HNSCC); immune balance; methylation; prognosis.