The m6A reader YTHDF1 promotes ovarian cancer progression via augmenting EIF3C translation

Abstract

N 6-Methyladenosine (m6A) is the most abundant RNA modification in mammal mRNAs and increasing evidence suggests the key roles of m6A in human tumorigenesis. However, whether m6A, especially its ‘reader’ YTHDF1, targets a gene involving in protein translation and thus affects overall protein production in cancer cells is largely unexplored. Here, using multi-omics analysis for ovarian cancer, we identified a novel mechanism involving EIF3C, a subunit of the protein translation initiation factor EIF3, as the direct target of the YTHDF1. YTHDF1 augments the translation of EIF3C in an m6A-dependent manner by binding to m6A-modified EIF3C mRNA and concomitantly promotes the overall translational output, thereby facilitating tumorigenesis and metastasis of ovarian cancer. YTHDF1 is frequently amplified in ovarian cancer and up-regulation of YTHDF1 is associated with the adverse prognosis of ovarian cancer patients. Furthermore, the protein but not the RNA abundance of EIF3C is increased in ovarian cancer and positively correlates with the protein expression of YTHDF1 in ovarian cancer patients, suggesting modification of EIF3C mRNA is more relevant to its role in cancer. Collectively, we identify the novel YTHDF1-EIF3C axis critical for ovarian cancer progression which can serve as a target to develop therapeutics for cancer treatment.

Insights into the Regulatory Role of m6A Epitranscriptome in Glioblastoma

“…Loss and gain functional studies confirmed that the reader YTHDF1 mediates m 6 A-increased translation of Snail mRNA [31]. Another recent report identified a novel mechanism involving the translation initiation factor EIF3C, as the direct target of the reader YTHDF1 [34]. YTHDF1 augments the translation of EIF3C by binding to m 6 A modified EIF3C mRNA and concomitantly promotes the overall translational output.…”

“…YTHDF1 augments the translation of EIF3C by binding to m 6 A modified EIF3C mRNA and concomitantly promotes the overall translational output. Global translation rates are generally enhanced in cancer cells and altered translational control is a fundamental response to oncogenic stimulation.m 6 A methylome analysis also identified that multiple translation initiation factors were modulated by m 6 A, indicating that m 6 A modification could directly regulate the expression of translation associated factors, thereby facilitating tumorigenesis and metastasis of ovarian cancer [34]. The expression of YTHDF1 was found to be induced by the oncogenic transcription factorc-MYC, and this axis c-MYC/YTHDF1 promotes colon cancer cell proliferation and induces the resistance against anticancer drugs [35].…”

m6A-binding proteins: the emerging crucial performers in epigenetics

“…EIF3C is a subunit of EIF3 which is indispensable for protein synthesis. YTHDF1 was highly expressed in ovarian cancer and targeted at EIF3C to enhance its translation efficiency via an m 6 A-dependent manner; therefore, affecting the overall translational output and regulating tumor cells proliferation, migration, and invasion [62].…”

“…Diminishing the abundance of PRR5, PRR5L, and mTOR [61] Ovarian cancer YTHDF1 EIF3C Targeting at EIF3C to enhance its translation efficiency [62] Cervical cancer YTHDF2 GAS5 Abrogating the GAS5 expression [63] Melanoma YTHDF2 PD-1 (PDCD1), CXCR4, SOX10…”

The prognostic value of METTL3 in cancer patients: a meta-analysis

“…The occurrence of m6A modi cation is encoded by methyltransferase complex. It can add, remove and read m6A sites respectively through the writer, eraser and reader [12][13][14][15].New evidences showed that by controlling the expression of oncogenes or tumor suppressor genes, m6A modi cation could regulate the occurrence, differentiation and metastasis of tumors [14,16,17]. METTL3 (methyltransferase like 3) is one of N6 methyladenosylmethy transferases, which plays an important role in mRNA pre-splicing, 3 '-terminal processing and translation regulation [18][19][20][21].According to recent studies, METTL3 can also in uence the tumorigenesis and growth of tumor by regulating the m6A modi cation [21][22][23].This mechanism has been found in a variety of tumor tissues [24][25][26].…”