METTL3 Promotes OSCC Progression by Down-Regulating WEE1 in a m6A-YTHDF2-Dependent Manner

Yongxu Su; Yanjia Hu; Binbin Qu; Rongchang Lei; Ge Guo

doi:10.1007/s12033-024-01165-y

METTL3 Promotes OSCC Progression by Down-Regulating WEE1 in a m6A-YTHDF2-Dependent Manner

Mol Biotechnol. 2024 May 14. doi: 10.1007/s12033-024-01165-y. Online ahead of print.

Authors

Yongxu Su¹, Yanjia Hu², Binbin Qu³, Rongchang Lei³, Ge Guo³

Affiliations

¹ Department of Oral and Maxilofacial Sugery, Changsha Stomatological Hospital, Changsha, 410004, Hunan, China. suyongxu@zsskqyy1.wecom.work.
² Department of Oral and Maxilofacial Sugery, Xiangya Stomatological Hospital Central South University, Changsha, 410000, Hunan, China.
³ Department of Oral and Maxilofacial Sugery, Changsha Stomatological Hospital, Changsha, 410004, Hunan, China.

PMID: 38744787
DOI: 10.1007/s12033-024-01165-y

Abstract

Oral squamous cell carcinoma (OSCC) is a common and highly lethal epithelial cancer. This study aimed to confirm the role of METTL3 in promoting OSCC and investigate its specific underlying mechanisms. Expression of the METTL3, YTH domain-containing family 2 (YTHDF2), and WEE1 were examined in normal oral epithelial cells and OSCC cells. Cell functions were examined after overexpressing WEE1 in OSCC cells. MeRIP-qPCR analysis was used to detect WEE1 m6A levels in HOK, SCC25, and CAL27 cells. WEE1 and its m6A levels were evaluated in OSCC cells by knocking down METTL3/YTHDF2, assessing the interaction between METTL3/YTHDF2 and WEE1. The impact of METTL3 and YTHDF2 downregulation on WEE1 mRNA stability was also investigated. The tumor weight and volume in a nude mouse model of OSCC after overexpression of WEE1 and YTHDF2 were measured. Expression of Ki-67 and WEE1 in OSCC tissue was detected using immunohistochemistry. Compared to normal oral epithelial cells, METTL3 and YTHDF2 were upregulated in OSCC cells, while WEE1 was downregulated, and there was a negative correlation between WEE1 and METTL3/YTHDF2 expression. WEE1 overexpression inhibited proliferation, invasion, and migration while promoting apoptosis in OSCC cells. METTL3 and YTHDF2 bound to WEE1 mRNA. METTL3/YTHDF2 knockdown increased WEE1 levels and WEE1 mRNA stability. METTL3 inhibition reduced WEE1 m6A levels. Inhibition of METTL3 weakened the interaction between YTHDF2 and WEE1 mRNA. In vivo, overexpression of WEE1 suppressed OSCC development, which was reversed by overexpression of YTHDF2. METTL3 facilitates the progression of OSCC through m6A-YTHDF2-dependent downregulation of WEE1.

Keywords: METTL3; OSCC; WEE1; YTHDF2; m6A.