The N(6)-methyladenosine (m6A) modification is the most pervasive modification of human RNAs. In recent years, an increasing number of studies have suggested that m6A likely plays important roles in cancers. Many studies have demonstrated that m6A is involved in the biological functions of cancer cells, such as proliferation, invasion, metastasis, and drug resistance. In addition, m6A is closely related to the prognosis of cancer patients. In this review, we highlight recent advances in understanding the function of m6A in various cancers. We emphasize the importance of m6A to cancer progression and look forward to describe future research directions. 

/pdf/role-of-m6a-writers-erasers-and-readers-in-cancer-1iiup12i.pdf

Role of m6A writers, erasers and readers in cancer

The progression of clear cell renal cell carcinoma (ccRCC) remains a major challenge in clinical practice, and elucidation of the molecular drivers of malignancy progression is critical for the development of effective therapeutic targets. Recent studies have demonstrated that N6-methyladenosine (m6A) is the most abundant modification of eukaryotic mRNA and plays a key role in tumorigenesis and progression. However, the biological roles and underlying mechanisms of m6A-mediated autophagy in cancers especially in ccRCC remain poorly elucidated. m6A dot blot assay, m6A RNA methylation assay kit and immunofluorescence analysis were used to profile m6A levels in tissue samples and their correlation with autophagic flux. Expression patterns and clinical significance of fat mass and obesity-associated protein (FTO) were determined through bioinformatics analysis, real-time PCR, western blotting, immunohistochemistry. RNA-seq, MeRIP-seq, MeRIP-qRT-PCR, RIP-qRT-PCR, transmission electron microscopy, immunofluorescence analysis and luciferase reporter assay were used to investigate the underlying mechanism of the FTO-autophagy axis. The role of FTO and autophagy in ccRCC progression was evaluated both in vitro and in vivo. Here we found that m6A modification was suppressed and closely related to autophagic flux in ccRCC. Elevated FTO was inhibited by rapamycin, whereas silencing FTO enhanced autophagic flux and impaired ccRCC growth and metastasis. SIK2 was identified as a functional target of m6A-mediated autophagy, thereby prompting FTO to play a conserved and important role in inhibiting autophagy and promoting tumorigenesis through an m6A-IGF2BP2 dependent mechanism. Moreover, the small molecule inhibitor FB23-2 targeting FTO inhibited tumor growth and prolonged survival in the patient-derived xenograft (PDX) model mice, suggesting that FTO is a potential effective therapeutic target for ccRCC. Our findings uncovered the crucial role of FTO/autophagy/SIK2 axis in modulating the progression of ccRCC, suggesting that FTO may serve as a valuable prognostic biomarker and promising therapeutic target in ccRCC.

/pdf/fto-mediated-autophagy-promotes-progression-of-clear-cell-1hqv7jez.pdf

FTO-mediated autophagy promotes progression of clear cell renal cell carcinoma via regulating SIK2 mRNA stability

Abstract Background N 6‐methyladenosine (m6A) is of great importance in renal physiology and disease progression, but its function and mechanism in renal fibrosis remain to be comprehensively and extensively explored. Hence, this study will explore the function and potential mechanism of critical regulator‐mediated m6A modification during renal fibrosis and thereby explore promising anti‐renal fibrosis agents. Methods Renal tissues from humans and mice as well as HK‐2 cells were used as research subjects. The profiles of m6A modification and regulators in renal fibrosis were analysed at the protein and RNA levels using Western blotting, quantitative real‐time polymerase chain reaction and other methods. Methylation RNA immunoprecipitation sequencing and RNA sequencing coupled with methyltransferase‐like 3 (METTL3) conditional knockout were used to explore the function of METTL3 and potential targets. Gene silencing and overexpression combined with RNA immunoprecipitation were performed to investigate the underlying mechanism by which METTL3 regulates the Ena/VASP‐like (EVL) m6A modification that promotes renal fibrosis. Molecular docking and virtual screening with in vitro and in vivo experiments were applied to screen promising traditional Chinese medicine (TCM) monomers and explore their mechanism of regulating the METTL3/EVL m6A axis and anti‐renal fibrosis. Results METTL3 and m6A modifications were hyperactivated in both the tubular region of fibrotic kidneys and HK‐2 cells. Upregulated METTL3 enhanced the m6A modification of EVL mRNA to improve its stability and expression in an insulin‐like growth factor 2 mRNA‐binding protein 2 (IGF2BP2)‐dependent manner. Highly expressed EVL binding to Smad7 abrogated the Smad7‐induced suppression of transforming growth factor‐β (TGF‐β1)/Smad3 signal transduction, which conversely facilitated renal fibrosis progression. Molecular docking and virtual screening based on the structure of METTL3 identified a TCM monomer named isoforsythiaside, which inhibited METTL3 activity together with the METTL3/EVL m6A axis to exert anti‐renal fibrosis effects. Conclusions Collectively, the overactivated METTL3/EVL m6A axis is a potential target for renal fibrosis therapy, and the pharmacological inhibition of METTL3 activity by isoforsythiaside suggests that it is a promising anti‐renal fibrosis agent.

Genetic and pharmacological inhibition of METTL3 alleviates renal fibrosis by reducing EVL m6A modification through an IGF2BP2‐dependent mechanism

The intensive interplay between aberrant epigenetic events and metabolic remodeling represents one of the hallmarks of tumors, including colon cancer. The functions of Bromodomain Containing Protein BRD‐9 in colon cancer remains indefinite. We aimed to identify the biological roles and clinical significance of BRD9 in colon cancer.

BRD9 is an essential regulator of glycolysis that creates an epigenetic vulnerability in colon adenocarcinoma

Uterine leiomyosarcoma (uLMS) is the most common type of uterine sarcoma associated with poor prognosis, high rates of recurrence, and metastasis. There is currently limited information about uLMS molecular mechanisms of origin and development. Bromodomain (BRD)-containing proteins are involved in many biological processes, most notably epigenetic regulation of transcription, and BRD protein dysfunction has been linked to many diseases including tumorigenesis. However, the role of BRD proteins in the pathogenesis of uLMS is unknown. Here, we show for the first time that BRD9 is aberrantly overexpressed in uLMS tissues compared to adjacent myometrium. BRD9 expression is also upregulated in uLMS cell lines compared to benign uterine fibroid and myometrium cell lines. Inhibition of BRD9 using the specific inhibitor (TP-472) suppressed uLMS cell proliferation via inducing apoptosis and cell cycle arrest. To further characterize the mechanistic basis for TP-472 inhibition of uLMS cell growth, we performed a comparative RNA-seq analysis of vehicle-treated and TP-472-treated uLMS cells (n = 4 each). Bioinformatics analysis revealed that TP-472 treatment distinctly altered the uLMS cell transcriptome. Gene set enrichment analysis identified critical pathways altered by BRD9 inhibition, including interferon-alpha response, KRAS signaling, MYC targets, TNF-a signaling via NFkB, and MTORC1 signaling. Parsimonious gene correlation network analysis identified nine enriched modules, including cell cycle and apoptosis modules. Moreover, the ENCODE Histone Modifications gene set and TargetScan microRNA analysis in Enrichr suggested that TP-472-induced BRD9 inhibition may alter the uLMS cell transcriptome by reprograming the oncogenic epigenome and inducing miRNA-mediated gene regulation. Therefore, BRD9 constitutes a specific vulnerability in malignant uLMS, and targeting non-BET BRD proteins in uLMS may provide a promising and novel strategy for treating patients with this aggressive uterine cancer.

/pdf/the-functional-role-and-regulatory-mechanism-of-bromodomain-3u6qdvl4.pdf

The Functional Role and Regulatory Mechanism of Bromodomain-Containing Protein 9 in Human Uterine Leiomyosarcoma

Hypoxia-inducible factor 2α (HIF2α) antagonists are effective against clear cell renal cell carcinomas (ccRCCs) that highly express HIF2α. To identify potential drug targets in HIF2αlow/− ccRCC, we...

Aberrant activation of m6A demethylase FTO renders HIF2α low/− clear cell renal cell carcinoma sensitive to BRD9 inhibitors

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Aberrant activation of m6A demethylase FTO renders HIF2α low/− clear cell renal cell carcinoma sensitive to BRD9 inhibitors