Cross-talk of four types of RNA modification writers defines tumor microenvironment and pharmacogenomic landscape in colorectal cancer

Abstract

Background The four major RNA adenosine modifications, i.e., m6A, m1A, alternative polyadenylation, and adenosine-to-inosine RNA editing, are mediated mostly by the “writer” enzymes and constitute critical mechanisms of epigenetic regulation in immune response and tumorigenesis. However, the cross-talk and potential roles of these “writers” in the tumor microenvironment (TME), drug sensitivity, and immunotherapy remain unknown. Methods We systematically characterized mRNA expression and genetic alterations of 26 RNA modification “writers” in colorectal cancer (CRC), and evaluated their expression pattern in 1697 CRC samples from 8 datasets. We used an unsupervised clustering method to assign the samples into two patterns of expression of RNA modification “writers”. Subsequently, we constructed the RNA modification “writer” Score (WM_Score) model based on differentially expressed genes (DEGs) responsible for the RNA modification patterns to quantify the RNA modification-related subtypes of individual tumors. Furthermore, we performed association analysis for WM_Score and characteristics of TME, consensus molecular subtypes (CMSs), clinical features, transcriptional and post-transcriptional regulation, drug response, and the efficacy of immunotherapy. Results We demonstrated that multi-layer alterations of RNA modification “writer” are associated with patient survival and TME cell-infiltrating characteristics. We identified two distinct RNA modification patterns, characterized by a high and a low WM_Score. The WM_Score-high group was associated with worse patient overall survival and with the infiltration of inhibitory immune cells, such as M2 macrophages, EMT activation, and metastasis, while the WM_Score-low group was associated with a survival advantage, apoptosis, and cell cycle signaling pathways. WM_Score correlated highly with the regulation of transcription and post-transcriptional events contributing to the development of CRC. In response to anti-cancer drugs, WM_Score highly negatively correlated (drug sensitive) with drugs which targeted oncogenic related pathways, such as MAPK, EGFR, and mTOR signaling pathways, positively correlated (drug resistance) with drugs which targeted in apoptosis and cell cycle. Importantly, the WM_Score was associated with the therapeutic efficacy of PD-L1 blockade, suggesting that the development of potential drugs targeting these “writers” to aid the clinical benefits of immunotherapy. Conclusions Our study is the first to provide a comprehensive analysis of four RNA modifications in CRC. We revealed the potential function of these writers in TME, transcriptional and post-transcriptional events, and identified their therapeutic liability in targeted therapy and immunotherapy. This work highlights the cross-talk and potential clinical utility of RNA modification “writers” in cancer therapy.

Overexpressed pseudogene MT1L associated with tumor immune infiltrates and indicates a worse prognosis in BLCA

“…TAMs can differentiate into M1 macrophages or M2 macrophages. Clinical research has shown that the poor prognosis of cancer patients significantly correlate with the number of M2 macrophages [45,46]. The correlation between MT1L expression and M2 macrophage surface marker expression in our study suggested that MT1L may be involved in macrophage polarization and partially explains the potential mechanism of poor prognosis in BLCA patients with high expression of MT1L.…”

Attention-based multi-label neural networks for integrated prediction and interpretation of twelve widely occurring RNA modifications

“…For example, by extending related studies 25 – 27 under the multi-label learning framework. Previously, due to the lack of epi-transcriptome datasets in matched biological conditions, cross-talk of multiple RNA modifications was mainly studied via the expression level of relevant RNA modification enzymes 51 . Although the interactions among different RNA modifications can partially be revealed from enzyme-based analysis, it is important to note that the known enzyme genes have multiple biological functions other than writing or erasing RNA modifications, which may contaminate the results.…”

Multiple Functions of RNA Methylation in T Cells: A Review

“…Since our observations regarding the cross-talk between RNA modifications in colorectal cancer highlighted their therapeutic liability toward immunotherapy (89), it would be interesting to decipher the existence of a similar complex regulatory network in T cells, and to determine whether other RNA methylations might function as a sort of "gas pedal" or "pace keeper" to control T cell clonal expansion, differentiation, and subsequent effector functions. The identification of a specific RNA epigenetic translational checkpoint will advance our knowledge concerning how different RNA methylations are sequentially coordinated to regulate T cell immunity.…”