METTL3 Promotes Tumorigenesis and Metastasis through BMI1 m6A Methylation in Oral Squamous Cell Carcinoma

Abstract

RNA modification plays an essential function in regulating gene expression and diverse biological processes. RNA modification enzyme methyltransferase-like 3 (METTL3) affects tumor progression by regulating the N 6 -methyladenosine (m 6 A) modification in the mRNAs of critical oncogenes or tumor suppressors, but its effect in oral squamous cell carcinoma (OSCC) remains unknown. In this study, we revealed that METTL3 was consistently upregulated in two OSCC cohorts, and high METTL3 expression was associated with poor prognosis. Functionally, cell proliferation, self-renewal, migration, and invasion ability in vitro and tumor growth and metastasis in vivo were decreased after METTL3 knockdown in OSCC cells. In contrast, the opposite results were obtained after METTL3 overexpression. In addition, the results obtained with the Mettl3 genetically modified mouse model validated the essential role of Mettl3 in chemical-induced oral carcinogenesis. In mechanism, methylated RNA immunoprecipitation sequencing (MeRIP-seq), MeRIP-quantitative real-time PCR, and luciferase reporter and mutagenesis assays identified that METTL3 mediates the m 6 A modification in the 3′ UTR of BMI1 mRNA. METTL3 promotes BMI1 translation in OSCC under the cooperation with m 6 A reader IGF2BP1. Our findings revealed that METTL3 promotes OSCC proliferation and metastasis through BMI1 m 6 A methylation, suggesting that the METTL3-m 6 A-BMI1 axis may serve as a prognostic biomarker or therapeutic target in patients with OSCC.

RNA-Binding Proteins as Regulators of Migration, Invasion and Metastasis in Oral Squamous Cell Carcinoma

“…The upregulation of METTL3 in oral cancer was also seen in two additional studies that also report a correlation of METTL3 expression with poor prognosis of OSCC patients [ 176 , 177 ]. Both studies detected similar cellular phenotypes, i.e., METTL3 promoted the proliferation, self-renewal, invasion, and migration of OSCC cells in vitro, as well as tumor growth and metastasis in vivo [ 176 , 177 ]. In addition, a genetically modified mouse model revealed an essential role of Mettl3 in chemical-induced oral carcinogenesis [ 176 ].…”

“…Both studies detected similar cellular phenotypes, i.e., METTL3 promoted the proliferation, self-renewal, invasion, and migration of OSCC cells in vitro, as well as tumor growth and metastasis in vivo [ 176 , 177 ]. In addition, a genetically modified mouse model revealed an essential role of Mettl3 in chemical-induced oral carcinogenesis [ 176 ]. However, both studies discovered varying mechanisms, which are not mutually exclusive and might simply reflect the overall diverse molecular targets and modes of action of METTL3 and/or m6A.…”

“…Alternatively, METTL3-catalysed methylation of epigenetic regulators might also represent a novel targeting option. Specifically, Liu and colleagues could show that METTL3 is responsible for the deposition of m6A marks in the 3′UTR of the B lymphoma Mo-MLV insertion region 1 homolog (BMI1) mRNA [ 176 ]. BMI1, a CSC marker and component of the Polycomb Repressive Complex 1 (PRC1) that is responsible for chromatin remodeling and epigenetic gene silencing, has been previously shown to promote chemoresistance and metastasis in HNSCC and plays an important role in the progression and prognosis of OSCC [ 178 ].…”

“…BMI1, a CSC marker and component of the Polycomb Repressive Complex 1 (PRC1) that is responsible for chromatin remodeling and epigenetic gene silencing, has been previously shown to promote chemoresistance and metastasis in HNSCC and plays an important role in the progression and prognosis of OSCC [ 178 ]. Here, METTL3, in cooperation with the m6A reader IGF2BP1, enhanced the translation of BMI1 in oral cancer cells, which is thought to underlie the observed cellular phenotypes upon METTL3 depletion or overexpression, although this remains to be formally proven [ 176 , 179 ]. Furthermore, the crosstalk between METTL3-dependent changes in epitranscriptome and their impact on the epigenetic modifications found in the oral cancer genome, including a potentially altered chromatin organization, need to be analyzed in more detail in the future.…”

Deficiency of Mettl3 in Bladder Cancer Stem Cells inhibits Bladder Cancer Progression and Angiogenesis

“…Upk3a CreER (JAX stock: 015855), K14 CreER (JAX stock: 005107) and C57BL/6J background mice were obtained from the Jackson Laboratory. Mettl3 ox/ ox and Mettl3 KI mice were obtained as previously described 26 . For induction of BCa, six to eight weeks old mice were treated with drinking water containing 500 µg/ml BBN for 16 weeks and then given normal water for another 10 weeks.…”