SUMOylation of YTHDF2 promotes mRNA degradation and cancer progression by increasing its binding affinity with m6A-modified mRNAs

Abstract

N 6-Methyladenosine (m6A) is the most abundant modification within diverse RNAs including mRNAs and lncRNAs and is regulated by a reversible process with important biological functions. Human YTH domain family 2 (YTHDF2) selectively recognized m6A-RNAs to regulate degradation. However, the possible regulation of YTHDF2 by protein post-translational modification remains unknown. Here, we show that YTHDF2 is SUMOylated in vivo and in vitro at the major site of K571, which can be induced by hypoxia while reduced by oxidative stress and SUMOylation inhibitors. SUMOylation of YTHDF2 has little impact on its ubiquitination and localization, but significantly increases its binding affinity of m6A-modified mRNAs and subsequently results in deregulated gene expressions which accounts for cancer progression. Moreover, Disease-free survival analysis of patients with lung adenocarcinoma derived from TCGA dataset reveals that higher expression of YTHDF2 together with higher expression of SUMO1 predicts poor prognosis. Our works uncover a new regulatory mechanism for YTHDF2 recognition of m6A-RNAs and highlight the importance of YTHDF2 SUMOylation in post-transcriptional gene expression regulation and cancer progression.

Main N6-Methyladenosine Readers: YTH Family Proteins in Cancers

“…In addition, post-translational modification plays an important role in regulating YTHDF family proteins. The SUMOylation of YTHDF2 at the major site of K571 significantly increases its binding affinity of m6Amodified mRNAs and results in deregulated gene expressions which accounts for cancer progression (94). Is there any other post-translational modification to regulate YTH family proteins and impact cancer progression?…”

Epitranscriptomic Approach: To Improve the Efficacy of ICB Therapy by Co-Targeting Intracellular Checkpoint CISH

“…However, selective depletion of ‘FTO’ not only increases sensitivity to anti-PD-1 therapy but also increases m6A methylation-inhibition of critical pro-tumorigenic (tumor-promoting) genes. Mechanistically, they proved that FTO-deficiency increases m6A-methylation at 5′UTR and 3′UTR of target genes; PD-1 (PDCD1), CXCR4 and SOX10, and thereby causing rapid mRNA-degradation by recruiting YTHDF2-reader proteins [ 155 , 157 , 158 ], confirmed by YTHDF2-knockdown in ‘increasing’ and YTHDF2-overexpression in ‘decreasing’ melanoma growth. Moreover, FTO-deficiency enhances the sensitivity of anti-PD-1 treatment by IFNγ-mediated cytokine response.…”

“…So far more than 160 chemical modifications have been identified [ 151 ] playing a crucial role in regulating various biological processes, for example, in acute myeloid leukemia treatment [ 125 ], lung adenocarcinoma [ 152 ] gastric cancer [ 153 ] and broad range tumor types [ 151 , 154 , 155 ]. The major epitranscriptomic machineries (writer/editor, eraser/remover and readers/effector [ 156 ] not only regulate RNAs by specific regulatory mechanism [ 157 , 158 ] but also decide the fate of the cells and its associated immune disorders in cellular context-dependent manner. In this section, we have described the clinical application of epitranscriptomics in overcoming the issues associated with ICB drug-resistance by combining personalized approach.…”

“…Interestingly, CRISPR/cas9-mediated deletion of Mettl-3/14 in colorectal cancer cell line (CT26) and murine melanoma cell line (B16) has not only increased cytotoxic CD8 + T-cell (CTL) infiltrations in the TME but also provided durable adoptive immune response. Mechanistically, they justified that, the loss of Mettl-3/14 augmented mRNA-stability of IFNγ, STAT-1 and IRF-1 by promoting IFNγ-STAT1-IRF1-signalling through YTHDF2 reader proteins [ 157 , 158 ], leading to prolong secretion of these cytokines in the TME, resulting in strong immune response. These investigations suggest the key role of Mettl-3/14 in inhibiting the efficacy of anti-PD-1 therapy by decreasing IFNγ, Cxcl-9 and Cxcl10-mediated immune response.…”

N6-methyladenosine-dependent signalling in cancer progression and insights into cancer therapies

“…YTHDF2 recognizes the m6A modification on RNA and recruits the CCR4-NOT multi-subunit deadenylase complex by interacting with CNOT1 to accelerate the deadenylation and degradation of RNA. Interestingly, the SUMOylation of YTHD F2 can enhance its ability to bind to m6A-mRNA, thereby promoting the degradation rate of mRNA [33]. However, phosphorylation at serine39 and threo-nine381 of YTHDF2 has been reported to stabilize the YTHDF2 protein [34].…”