RESUMO
Human papillomavirus (HPV) infection is a causative agent of cervical cancer (CC). N6-methyladenosine (m6A) modification is implicated in carcinogenesis and tumor progression. However, the involvement of m6A modification in HPV-involved CC remains unclear. Here we showed that HPV E6/7 oncoproteins affected the global m6A modification and E7 specifically promoted the expression of ALKBH5. We found that ALKBH5 was significantly upregulated in CC and might serve as a valuable prognostic marker. Forced expression of ALKBH5 enhanced the malignant phenotypes of CC cells. Mechanistically, we discovered that E7 increased ALKBH5 expression through E2F1-mediated activation of the H3K27Ac and H3K4Me3 histone modifications, as well as post-translational modification mediated by DDX3. ALKBH5-mediated m6A demethylation enhanced the expression of PAK5. The m6A reader YTHDF2 bound to PAK5 mRNA and regulated its stability in an m6A-dependent manner. Moreover, ALKBH5 promoted tumorigenesis and metastasis of CC by regulating PAK5. Overall, our findings herein demonstrate a significant role of ALKBH5 in CC progression in HPV-positive cells. Thus, we propose that ALKBH5 may serve as a prognostic biomarker and therapeutic target for CC patients.
Assuntos
Infecções por Papillomavirus , Neoplasias do Colo do Útero , Feminino , Humanos , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologia , Infecções por Papillomavirus/genética , Carcinogênese/genética , Homólogo AlkB 5 da RNA Desmetilase/genética , Homólogo AlkB 5 da RNA Desmetilase/metabolismoRESUMO
Due to poor T cell infiltration, tumors evade immune surveillance. Increased CD8+ T cell infiltration in breast cancer suggests a satisfactory response to immunotherapy. COPS6 has been identified as an oncogene, but its role in regulating antitumor immune responses has not been defined. In this study, we investigated the impact of COPS6 on tumor immune evasion in vivo. Tumor transplantation models were established in C57BL/6 J mice and BALB/c nude mice. Flow cytometry was conducted to identify the role of COPS6 on tumor-infiltrating CD8+ T cells. By analyzing the TCGA and GTEx cohort, we found that COPS6 expression was significantly up-regulated in a variety of cancers. In human osteosarcoma cell line U2OS and non-small cell lung cancer cell line H1299, we showed that p53 negatively regulated COPS6 promoter activity. In human breast cancer MCF-7 cells, COPS6 overexpression stimulated p-AKT expression as well as the proliferation and malignant transformation of tumor cells, whereas knockdown of COPS6 caused opposite effects. Knockdown of COPS6 also significantly suppressed the growth of mouse mammary cancer EMT6 xenografts in BALB/c nude mice. Bioinformatics analysis suggested that COPS6 was a mediator of IL-6 production in the tumor microenvironment and a negative regulator of CD8+ T cell tumor infiltration in breast cancer. In C57BL6 mice bearing EMT6 xenografts, COPS6 knockdown in the EMT6 cells increased the number of tumor-infiltrating CD8+ T cells, while knockdown of IL-6 in COPS6KD EMT6 cells diminished tumor infiltrating CD8+ T cells. We conclude that COPS6 promotes breast cancer progression by reducing CD8+ T cell infiltration and function via the regulation of IL-6 secretion. This study clarifies the role of p53/COPS6/IL-6/CD8+ tumor infiltrating lymphocytes signaling in breast cancer progression and immune evasion, opening a new path for development of COPS6-targeting therapies to enhance tumor immunogenicity and treat immunologically "cold" breast cancer.
Assuntos
Neoplasias da Mama , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Animais , Camundongos , Feminino , Linfócitos T CD8-Positivos/metabolismo , Neoplasias da Mama/patologia , Interleucina-6/metabolismo , Camundongos Nus , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Evasão Tumoral , Proteína Supressora de Tumor p53/metabolismo , Neoplasias Pulmonares/patologia , Camundongos Endogâmicos C57BL , Microambiente Tumoral , Linhagem Celular Tumoral , Complexo do Signalossomo COP9/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismoRESUMO
OBJECTIVE: Serine hydroxymethyltransferase 2 (SHMT2) is the first rate-limiting enzyme for serine/glycine biosynthesis and one carbon metabolism. Here, we explore the underlying mechanism of how SHMT2 functions in renal cell carcinoma (RCC) initiation. METHODS: In this study, SHMT2 expression was assessed in RCC tissues. In vitro experiments were performed to investigate the functional role of SHMT2. The detailed mechanisms of SHMT2-mediated PPAT were addressed. RESULTS: Increased SHMT2 facilitated RCC cell proliferation by inducing the G1/S phase transition. And SHMT2 promoted the expression of PPAT. Mechanism dissection revealed that SHMT2 enhanced the m6A modification through the endogenous methyl donor SAM mediated by SHMT2 via serine/glycine one carbon metabolic networks. SHMT2-catalyzed serine/glycine conversion regulated PPAT expression in an m6A-IGF2BP2-dependent manner. SHMT2 promoted RCC cell proliferation by upregulating PPAT expression. CONCLUSIONS: SHMT2 promotes RCC tumorigenesis by increasing PPAT expression. Thus, SHMT2 may be a novel potential therapeutic target for RCC.
Assuntos
Amidofosforribosiltransferase , Carcinoma de Células Renais , Glicina Hidroximetiltransferase , Neoplasias Renais , Amidofosforribosiltransferase/metabolismo , Carbono/metabolismo , Carcinogênese/genética , Carcinoma de Células Renais/genética , Proliferação de Células , Transformação Celular Neoplásica , Glicina/metabolismo , Glicina Hidroximetiltransferase/genética , Glicina Hidroximetiltransferase/metabolismo , Humanos , Neoplasias Renais/genética , Proteínas de Ligação a RNA/metabolismo , Serina/metabolismoRESUMO
The insulin-like growth factor-2 mRNA-binding proteins (IGF2BPs) pertain to a highly conservative RNA-binding family that works as a post-transcriptional fine-tuner for target transcripts. Emerging evidence suggests that IGF2BPs regulate RNA processing and metabolism, including stability, translation, and localization, and are involved in various cellular functions and pathophysiologies. In this review, we summarize the roles and molecular mechanisms of IGF2BPs in cancer development and progression. We mainly discuss the functional relevance of IGF2BPs in embryo development, neurogenesis, metabolism, RNA processing, and tumorigenesis. Understanding IGF2BPs role in tumor progression will provide new insight into cancer pathophysiology.
Assuntos
Carcinogênese/patologia , Fator de Crescimento Insulin-Like II/metabolismo , Proteínas de Ligação a RNA/metabolismo , Desenvolvimento Embrionário/fisiologia , Metabolismo Energético/fisiologia , Humanos , Neoplasias/fisiopatologia , Neurogênese/fisiologia , RNA Mensageiro/metabolismoRESUMO
Background N6-methyladenosine (m6A), the most prevalent internal mRNA modification in eukaryotes, is added by m6A methyltransferases, removed by m6A demethylases and recognised by m6A-binding proteins. This modification significantly influences carious facets of RNA metabolism and plays a pivotal role in cellular and physiological processes. Main body Pre-mRNA alternative splicing, a process that generates multiple splice isoforms from multi-exon genes, contributes significantly to the protein diversity in mammals. Moreover, the presence of crosstalk between m6A modification and alternative splicing, with m6A modifications on pre-mRNAs exerting regulatory control, has been established. The m6A modification modulates alternative splicing patterns by recruiting specific RNA-binding proteins (RBPs) that regulate alternative splicing or by directly influencing the interaction between RBPs and their target RNAs. Conversely, alternative splicing can impact the deposition or recognition of m6A modification on mRNAs. The integration of m6A modifications has expanded the scope of therapeutic strategies for cancer treatment, while alternative splicing offers novel insights into the mechanistic role of m6A methylation in cancer initiation and progression. Conclusion This review aims to highlight the biological functions of alternative splicing of m6A modification machinery and its implications in tumourigenesis. Furthermore, we discuss the clinical relevance of understanding m6A-dependent alternative splicing in tumour therapies.
Assuntos
Processamento Alternativo , Neoplasias , Animais , Processamento Alternativo/genética , Neoplasias/genética , RNA/metabolismo , Metilação , RNA Mensageiro/genética , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Mamíferos/genética , Mamíferos/metabolismoRESUMO
N6-methyladenosine (m6A) RNA methylation is profoundly involved in epigenetic regulation, especially for carcinogenesis and tumor progression. Mounting evidence suggests that methyltransferase METTL3 regulates malignant behaviors of gastric cancer (GC). However, the clinical significance and biological implication of SPHK2 and its related m6A modification in GC remain unclear. In this study, quantitative real-time PCR (qRT-PCR), western blot and immunohistochemistry were utilized to detect the expression profiles and prognostic significance of SPHK2 in GC. Here, we showed that increased SPHK2 was signified a poor prognosis of GC patients. Phosphorylation and ubiquitination assays were used to investigate the possible mechanisms of SPHK2-mediated KLF2 expression. SPHK2 can promote the phosphorylation of KLF2, which triggers the ubiquitination and degradation of KLF2 protein in GC. Methylated RNA immunoprecipitation (MeRIP) was performed to uncover the m6A modification of SPHK2 mRNA. METTL3 promotes translation of SPHK2 mRNA via an m6A-YTHDF1-dependent manner. Functionally, SPHK2 facilitates GC cell proliferation, migration and invasion by inhibiting KLF2 expression. SPHK2/KLF2 regulates the cell proliferation, migration, and invasion induced by METTL3 in GC. Overall, our findings reveal that METTL3-mediated m6A modification of SPHK2 contributes to GC progression, which extends the understanding of the importance m6A methylation in GC and represents a potential target for GC therapy.
Assuntos
Fatores de Transcrição Kruppel-Like/metabolismo , Metiltransferases/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Neoplasias Gástricas/metabolismo , Fatores de Transcrição/metabolismo , Proliferação de Células/fisiologia , Progressão da Doença , Humanos , Metilação , Fosforilação , Neoplasias Gástricas/patologiaRESUMO
N6-methyladenosine (m6A) is identified as the most prevalent and abundant internal RNA modification, especially within eukaryotic mRNAs, which has attracted much attention in recent years since its importance for regulating gene expression and deciding cell fate. m6A modification is installed by RNA methyltransferases METTL3, METTL14 and WTAP (Writers), removed by the demethylases FTO and ALKBH5 (Erasers) and recognized by m6A binding proteins, such as YT521-B homology YTH domain-containing proteins (Readers). Accumulating evidence shows that m6A RNA methylation participates in almost all aspects of RNA processing, implying an association with important bioprocesses. In this review, we mainly summarize and discuss the functional relevance and importance of m6A modification in cellular processes.
Assuntos
Adenosina/análogos & derivados , RNA/química , RNA/genética , Adenosina/química , Animais , Regulação da Expressão Gênica , Humanos , Biossíntese de Proteínas , Splicing de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
N6 -methyladenosine (m6 A) RNA modification, first discovered in 1974, is the most prevalent, abundant and penetrating messenger RNA (mRNA) modification in eukaryotes. This governs the fate of modified transcripts, regulates RNA metabolism and biological processes, and participates in pathogenesis of numerous human diseases, especially in cancer through the reciprocal regulation of m6 A methyltransferases ("writers") and demethylases ("erasers") and the binding proteins decoding m6 A methylation ("readers"). Accumulating evidence indicates a complicated regulation network of m6 A modification involving multiple m6 A-associated regulatory proteins whose biological functions have been further analysed. This review aimed to summarize the current knowledge on the potential significance and molecular mechanisms of m6 A RNA modification in the initiation and progression of cancer.