Integrative Analyses of m6A Regulators Identify that METTL3 is Associated with HPV Status and Immunosuppressive Microenvironment in HPV-related Cancers

Abstract

Although m6A modifications are associated with tumor progression, and anti-tumor immune responses, the role of m6A regulators in HPV-related carcinogenesis has not been well resolved. To provide evidence for the role of m6A regulators in HPV-related carcinogenesis and identify potential therapeutic targets for HPV-related cancers, integrative analyses of m6A regulators in 1,485 head and neck squamous cell carcinoma (HNSC) patients and 507 cervical squamous cell carcinoma (CESC) patients was performed and identified that an m6A regulator, METTL3, was highly expressed in tumors and was related to the poor prognosis in HNSC and CESC. In HPV-positive tumors, METTL3 was positively associated with tumor HPV status, such as HPV integration status, E6 and unspliced-E6 expression, and p16 expression. Further analysis demonstrated that METTL3 high status was negatively correlated with tumor immune cell infiltrations and facilitated the expression of immunosuppressive immune checkpoint molecules (i.e., PD-L1). Cell-derived xenograft models demonstrated that METTL3 inhibitor combined with anti-PD1 therapy promoted immunotherapy of CESC in vivo. Overall, this study identified that METTL3 high status, is associated with poor prognosis and HPV status, and serves as a mediator of the immunosuppressive tumor microenvironment in HPV-associated cancer, which provides a promising therapeutic target for anti-cancer immunotherapy.

Upregulation of LRRC8A by m5C modification-mediated mRNA stability suppresses apoptosis and facilitates tumorigenesis in cervical cancer

“…S6 C). Interestingly, recent research unveiled that high expression of the N6-methyladenosine methyltransferase METTL3 is associated with HPV status and CC patients' poor prognosis 46 . Thus, the relationship between RNA modifications including the m 5 C modification and HPV-infection needs more investigations.…”

The regulation of N6‐methyladenosine modification in PD‐L1‐induced anti‐tumor immunity

“…STM2457 emerged with a higher‐fold selectivity for METTL3 and showed no inhibition of other RNA methyltransferases in acute myeloid leukemia (AML) treatment 23 . Further research confirmed that suppression of METTL3 with the employment of STM2457 significantly enhances the inhibition of tumor progression in subcutaneous tumor mouse models together with anti‐PD‐1 therapy in HPV‐related cervical squamous cell carcinoma 93 …”

“…23 Further research confirmed that suppression of METTL3 with the employment of STM2457 significantly enhances the inhibition of tumor progression in subcutaneous tumor mouse models together with anti-PD-1 therapy in HPV-related cervical squamous cell carcinoma. 93 The research on ALKBH5 inhibitors is still limited. Some studies have emerged identifying ALKBH5 inhibitors, including MV-1035 94 and 5-hydroxy-1-(4-((Nmethylsulfamoyl)methyl)phenyl)-1H-pyrazole-3-carboxylic acid.…”

The role of RNA methyltransferase METTL3 in gynecologic cancers: Results and mechanisms

“…The regulatory protein of m6A methylation is closely linked to the HPV infection status of patients with CC, as it affects the extent of m6A methylation modification ( Condic et al, 2022 ). Mettl3 is significantly overregulated in HPV-positive CC tissues and correlates with immune checkpoints and infiltration ( Table 1 ) ( Yu et al, 2022 ). The relationship between m6A methylation and HPV infection-associated CC needs further investigation.…”

“…Compared to patients with early-stage CC, Mettl3 expression levels were significantly higher in patients with advanced CC, suggesting a gradual increase in Mettl3 during the process of tumor malignancy ( Hu et al, 2020 ; Shen et al, 2022a ). The occurrence of CC is closely associated with HPV infection status, and previous studies have investigated the correlation between Mettl3 and HPV infection status, potentially offering a new avenue for the prevention, early diagnosis, and treatment of CC ( Goodman, 2015 ; Yu et al, 2022 ). In addition, developing immune checkpoint inhibitors in recent years has significantly benefited cancer patients.…”