The M6A methyltransferase METTL3: acting as a tumor suppressor in renal cell carcinoma

Abstract

We aimed to study the role of METTL3 in renal cell carcinoma (RCC) carcinogenesis and development. Immunohistochemistry was performed in clinical tissue microarray. Expression level of METTL3 in RCC tissues and cell lines was evaluated by quantitative real-time PCR (qRT-PCR) and western blot. Then, the effects of METTL3 on proliferation, migration, invasion and cell cycle were studied in RCC cells. Additionally, in vivo study was carried out in nude mice. Negative METTL3 expression was associated with larger tumor size (P=0.010) and higher histological grade (P=0.021). Moreover, RCC patients with positive METTL3 expression had an obvious longer survival time (P=0.039). METTL3 mRNA and protein expression was lower in RCC samples compared with adjacent non-tumor samples, and lower in RCC cell lines (CAKI-1, CAKI-2 and ACHN) compared with HK-2. Afterwards, knockdown of METTL3 could obviously promote cell proliferation, migration and invasion function, and induce G0/G1 arrest. In contrast, up-regulation of METTL3 could inhibit such functions and reduce G0/G1 arrest. Additionally, up-regulation of METTL3 significantly suppressed tumor growth in vivo. Furthermore, significant changes in epithelial-to-mesenchymal transition (EMT) and PI3K-Akt-mTOR pathways were observed. Overall, our findings demonstrated that METTL3 might have a carcinostasis role in cell proliferation, migration, invasion function and cell cycle of RCC, indicating METTL3 may act as a novel marker for tumorigenesis, development and survival of RCC.

Global analysis of N6-methyladenosine functions and its disease association using deep learning and network-based methods

“…Also, m 6 A is predicted to have a role in renal cell carcinoma. This is also corroborated by Xiao et al [74], which reported that the m 6 A methyltransferase METTL3 acted as a tumor suppressor in renal cell carcinoma and publications in [75,76], which identified YTHDF2, an m 6 A binding protein, to be involved in renal cell carcinoma. Taken together, we found existing evidence to support 3 out of 5 predicted association diseases.…”

Methyltransferase like 3 promotes colorectal cancer proliferation by stabilizing CCNE1 mRNA in an m6A‐dependent manner

“…29 METTL3 acted as a tumour suppressor in renal cell carcinoma cells to regulate cell cycle arrest in G1 phase by targeting PI3K/Akt/mTOR signalling pathway. 34 In CRC, a recent research has verified that METTL3 could promote cell self-renewal, stem cell frequency and migration through an m6A-IGF2BP2-dependent mechanism. 37 However, another study showed that METTL3 could suppress colorectal cancer proliferation and migration through p38/ERK pathways.…”

“…For example, METTL3 was identified as an essential oncogene to promote cell cycles and growth in acute myeloid leukaemia by targeting transcription factor SP1 . METTL3 acted as a tumour suppressor in renal cell carcinoma cells to regulate cell cycle arrest in G1 phase by targeting PI3K/Akt/mTOR signalling pathway …”

“…23 Recent studies showed that m6A modification played essential roles in tissue development, stem cell formation and differentiation, 24,25 control of heat shock response 26 and circadian clock controlling, 27 as well as in tumours formation. [28][29][30][31][32][33][34][35] As the critical m6A methyltransferase, the role of METTL3 in tumours is controversial.…”

The Role of Dynamic m6A RNA Methylation in Photobiology

“…Lin and colleagues showed that METTL3 promotes translation of oncogenic factors such as the epidermal growth factor receptor (EGFR) in LUAD cells through a mechanism independent of its methyltransferase activity (89). In contrast, METTL3/METTL14 downregulation was also shown to be associated with glioblastoma (GBM), hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC) (92)(93)(94). Upregulation of METTL3 suppressed RCC tumor growth in xenografted mice, and higher METTL3 expression was associated with significantly better prognosis in RCC patients (94).…”