m6A methyltransferase KIAA1429 accelerates oral squamous cell carcinoma via regulating glycolysis and ferroptosis

N⁶-methyladenosine (m⁶A) modification acts as the most prevalent modification on eukaryotic RNA, and its function on oral squamous cell carcinoma (OSCC) is still unclear. Here, the present research aimed to explore the novel function of m⁶A methyltransferase KIAA1429 in OSCC. Results illustrated that KIAA1429 up-regulated in the OSCC samples and cells. Gain/loss functional assays demonstrated that KIAA1429 repressed the ferroptosis of OSCC. Moreover, KIAA1429 positively accelerated the aerobic glycolysis of OSCC, including glucose uptake, lactate production, ATP level and ECAR. Mechanistically, KIAA1429 could install the m⁶A modification on the PGK1 mRNA, thereby up-regulating the methylated m⁶A level. Moreover, m⁶A reader YTHDF1 recognized the m⁶A modification site of PGK1 mRNA and enhanced its mRNA stability. Thus, KIAA1429 promoted the OSCC aerobic glycolysis and inhibited the ferroptosis of OSCC through YTHDF1-mediated PGK1 mRNA stability. Taken together, these findings reveal a novel insight for KIAA1429 on OSCC via m⁶A-dependent manner.     

Exosomal miRNA-223-3p derived from tumor associated macrophages promotes pulmonary metastasis of breast cancer 4T1 cells

Research about the effect of exosomes derived from tumor associated macrophages (TAM-exos) in the distant organ metastasis of breast cancer is limited. In this study, we found that TAM-exos could promote the migration of 4T1 cells. Through comparing the expression of microRNAs in 4T1 cells, TAM-exos, and exosomes from bone marrow derived macrophages (BMDM-exos) by sequencing, miR-223-3p and miR-379-5p were screened out as two noteworthy differentially expressed microRNAs. Furthermore, miR-223-3p was confirmed to be the reason for the improved migration and metastasis of 4T1 cells. The expression of miR-223-3p was also increased in 4T1 cells isolated from the lung of tumor-bearing mice. Cbx5, which has been reported to be closely related with metastasis of breast cancer, was identified to be the target of miR-223-3p. Based on the information of breast cancer patients from online databases, miR-223-3p had a negative correlation with the overall survival rate of breast cancer patients within a three-year follow-up, while Cbx5 showed an opposite relationship. Taken together, miR-223-3p in TAM-exos can be delivered into 4T1 cells and exosomal miR-223-3p promotes pulmonary metastasis of 4T1 cells by targeting Cbx5.     

A new m6A methylation-related gene signature for prognostic value in patient with urothelial carcinoma of the bladder

Background: Bladder cancer (BC) is one of the most common malignant urological cancer in the world. Because of its characteristic of easy-recurrence and muscle-invasive, advances in our genetic understanding of bladder cancer should be translated into prognostic indicators.Methods: We investigated 16 m⁶A RNA methylation regulators from The Cancer Genome Atlas (TCGA) database and The Human Protein Atlas (HPA) database. The expression profile, clinical application as well as prognostic value of these genes in UC were investigated. Moreover, we further explored the correlation between RNA methylation genes and biological functions, pathways and immune status.Results: Five m⁶A-related genes (HNRNPC, YTHDF2, YTHDF1, HNRNPA2B1, METTL3) up-regulated in UC tissues, while three regulators (ZC3H13, METTL16, FTO) down-regulated in UC. FTO and YTHDF2 show biomarker potential for the prognosis of UC patients. In addition, these identified genes may related with essential functions and core molecular pathways.Conclusions: Our research shows that two m⁶A RNA methylation regulators can serve as reliable prognostic biomarkers of UC, which might be exerted as potential targets of therapeutic strategies.     

RNA m6A reader YTHDF2 facilitates lung adenocarcinoma cell proliferation and metastasis by targeting the AXIN1/Wnt/β-catenin signaling

Lung adenocarcinoma (LUAD) remains a leading cause of cancer-related deaths worldwide. YTHDF2 is a reader of N⁶-methyladenosine (m⁶A) on RNA and plays a critical role in the initiation and propagation of myeloid leukemia; however, whether YTHDF2 controls the development of LUAD remains to be explored. Here, we found that YTHDF2 was significantly upregulated in LUAD compared with paracancerous normal tissues, and YTHDF2 knockdown drastically inhibited, while its overexpression promoted, cell growth, colony formation and migration of LUAD cells in vitro. In addition, YTHDF2 knockdown significantly inhibited tumorigenesis in a murine tumor xenograft model. Through the integrative analysis of RNA-seq, m⁶A-seq, CLIP-seq, and RIP-seq datasets, we identified a set of potential direct targets of YTHDF2 in LUAD, among which we confirmed AXIN1, which encodes a negative regulator of the Wnt/β-catenin signaling, as a direct target of YTHDF2. YTHDF2 promoted AXIN1 mRNA decay and subsequently activated the Wnt/β-catenin signaling. Knockout of AXIN1 sufficiently rescued the inhibitory effect of YTHDF2 depletion on lung cancer cell proliferation, colony-formation, and migration. These results revealed YTHDF2 to be a contributor of LUAD development acting through the upregulation of the AXIN1/Wnt/β-catenin signaling, which can be a potential therapeutic target for LUAD.Subject terms: DNA methylation, Non-small-cell lung cancer     

N6-甲基腺苷修饰(m6A)在乳腺癌中的研究进展

乳腺癌是女性最常见的癌症之一,也是导致女性癌症死亡的最主要原因.尽管早期乳腺癌的治疗已经取得了极大进展,但晚期伴转移乳腺癌治疗效果较差,具有高复发率和高死亡率.因此,鉴定新的用于诊断和预测乳腺癌转移的分子标记、开发新的治疗策略成为迫切需要.近年来,mRNA的异常N⁶-甲基腺苷修饰(N⁶-methyladenosine,m⁶A)对癌基因功能和表达水平的表观遗传学调控逐渐成为恶性乳腺癌研究的焦点.本文分析和总结了m⁶A甲基化修饰及其调节蛋白参与调控乳腺癌发生发展的最新研究进展,以期为乳腺癌中m⁶A甲基化修饰研究提供新的思路和参考,进一步为乳腺癌的诊断、治疗、预后及监测提供新的有效策略.     

Bone marrow mesenchymal stem cells-derived exosomal microRNA-16-5p restrains epithelial-mesenchymal transition in breast cancer cells via EPHA1/NF-κB signaling axis

ObjectiveThis study intends to conquer the mystery of microRNA-16-5p/erythropoietin-producing hepatocellular A1/nuclear factor-κB signaling (miR-16-5p/EPHA1/NF-κB signaling) in breast cancer.MethodsExpression of miR-16-5p, EPHA1 and NF-κB signaling-related proteins were detected. Gene overexpression or silencing was used to examine the biological roles of bone marrow mesenchymal stem cells (BMSCs)-derived exo-miR-16-5p in breast cancer. The effect of exo-miR-16-5p on tumorigenesis of breast cancer was confirmed by the xenograft nude mouse model.ResultsLow miR-16-5p and high EPHA1 expression were examined in breast cancer. BMSCs-derived exosomes, up-regulated miR-16-5p or down-regulated EPHA1 restrained epithelial-mesenchymal transition (EMT) of breast cancer cells and tumor growth in nude mice. Down-regulated miR-16-5p or up-regulated EPHA1 activated NF-κB signaling. Knockdown of EPHA1 or inhibition of NF-κB signaling reversed the effects of down-regulated miR-16-5p on breast cancer cells.ConclusionBMSCs-derived exosomal miR-16-5p hinders breast cancer cells progression via EPHA1/NF-κB signaling axis.     

The functional roles of m6A modification in T lymphocyte responses and autoimmune diseases

RNA N6-methyladenosine (m⁶A) modification is abundant in eukaryotes, bacteria and archaea. It is an RNA modification mainly existing in messenger RNA (mRNAs) and has a significant effect on the metabolism and function of mRNAs. m⁶A modification is controlled by three types of proteins, namely methyltransferase as the “writers”, demethylase as the “erasers”, and specific m⁶A recognized protein (YTHDF1–3) as the “readers”. Recent studies have shown that m⁶A modification plays an important role in cancer, viral infection and autoimmune diseases. In this review, we will elaborate on the m⁶A modifications in the homeostasis and differentiation of T cells. Then we will further summarize the effects of m⁶A modification on the T cell responses and T cell-mediated autoimmune diseases. This will advance T cell epigenetics research and provide potential biomarkers and therapeutic targets for autoimmune diseases.     

YTHDF1 promotes breast cancer cell growth,DNA damage repair and chemoresistance

Chemoresistance represents a major obstacle to the treatment of human cancers. Increased DNA repair capacity is one of the important mechanisms underlying chemoresistance. In silico analysis indicated that YTHDF1, an m6A binding protein, is a putative tumor promoter in breast cancer. Loss of function studies further showed that YTHDF1 promotes breast cancer cell growth in vitro and in vivo. YTHDF1 facilitates S-phase entry, DNA replication and DNA damage repair, and accordingly YTHDF1 knockdown sensitizes breast cancer cells to Adriamycin and Cisplatin as well as Olaparib, a PARP inhibitor. E2F8 is a target molecule by YTHDF1 which modulates E2F8 mRNA stability and DNA damage repair in a METTL14-dependent manner. These data demonstrate that YTHDF1 has a tumor-promoting role in breast cancer, and is a novel target to overcome chemoresistance.Subject terms: Breast cancer, Breast cancer