N7-methylguanosine tRNA modification promotes esophageal squamous cell carcinoma tumorigenesis via the RPTOR/ULK1/autophagy axis

Abstract

Mis-regulated RNA modifications promote the processing and translation of oncogenic mRNAs to facilitate cancer progression, while the molecular mechanisms remain unclear. Here we reveal that tRNA m7G methyltransferase complex proteins METTL1 and WDR4 are significantly up-regulated in esophageal squamous cell carcinoma (ESCC) tissues and associated with poor ESCC prognosis. In addition, METTL1 and WDR4 promote ESCC progression via the tRNA m7G methyltransferase activity in vitro and in vivo. Mechanistically, METTL1 or WDR4 knockdown leads to decreased expression of m7G-modified tRNAs and reduces the translation of a subset of oncogenic transcripts enriched in RPTOR/ULK1/autophagy pathway. Furthermore, ESCC models using Mettl1 conditional knockout and knockin mice uncover the essential function of METTL1 in promoting ESCC tumorigenesis in vivo. Our study demonstrates the important oncogenic function of mis-regulated tRNA m7G modification in ESCC, and suggest that targeting METTL1 and its downstream signaling axis could be a promising therapeutic target for ESCC treatment.

Celastrol Inhibited Human Esophageal Cancer by Activating DR5-Dependent Extrinsic and Noxa/Bim-Dependent Intrinsic Apoptosis

“…Major limitations of the treatment of ESCC include high toxicity and acquired therapeutic resistance to chemotherapy and radiotherapy, as well as the high recurrence rate of surgery ( Leng et al, 2020 ). In recent years, although some clinical advances have been made in the development of diagnosis and therapeutic techniques, the overall 5-year survival rate for ESCC patients is still very poor ( Han et al, 2022 ). Consequently, it is pressingly needed to facilitate the development of effective strategies for ESCC therapy.…”

The potential role of N7-methylguanosine (m7G) in cancer

“…Intriguingly, regulators of the m7G modification are aberrantly expressed in various cancers and may act as novel biomarkers for diagnosis and prognostic prediction. The m7G regulator METTL1 is significantly overexpressed and promotes tumorigenesis and development in AML, BC, ESCC, glioma, HCC, HNSCC, ICC, LC, and NPC, and high expression levels of METTL1 often predict poor survival in these patients [ 26 , 43 , 52 , 56 , 59 , 60 , 66 , 68 , 78 ]. WDR4 is also highly expressed and increases malignant phenotypes in multiple malignancies, including AML, ESCC, HCC, HNSCC, IC, LC, and NPC.…”

“…WDR4 is also highly expressed and increases malignant phenotypes in multiple malignancies, including AML, ESCC, HCC, HNSCC, IC, LC, and NPC. Increased expression of WDR4 is regarded as an unfavorable prognostic biomarker in such cancers [ 24 , 43 , 52 , 59 , 66 , 68 , 78 ]. In addition, METTL1 expression is associated with extremely poor prognosis in KIRC and mesothelioma, while it is related to superior survival in patients with ovarian serous cystadenocarcinoma [ 56 ].…”

“…The m7G regulators perform different roles in different types of tumors. For example, METTL1 and WDR4 play a strong carcinogenic role in AML, BC, ESCC, glioma, HCC, HNSCC, ICC, LC, and NPC, promoting the malignant phenotype and progression of tumors [ 24 , 26 , 43 , 52 , 56 , 59 , 60 , 66 , 68 , 78 ]; however, METTL1 exerts a significant anti-cancer effect in CC [ 48 ]. WBCCR22 restrains PC development, while accelerating glioma progression [ 57 , 80 ].…”

“…Esophageal squamous cell carcinoma (ESCC) is highly susceptible to lymph node metastasis and vascular invasion, and patients with ESCC are often diagnosed at an advanced stage, creating the need for the development of additional treatment strategies [ 51 ]. A recent study revealed that the expression of METTL1 and WDR4 is aberrantly upregulated in ESCC, which is also associated with inferior clinical outcomes in patients with ESCC [ 52 ]. Inhibition of METTL1 or WDR4 is an effective method to decrease ESCC progression both in vitro and in vivo, including impairing tumor proliferative capacity and tumor formation.…”