KIAA1429 facilitates progression of hepatocellular carcinoma by modulating m6A levels in HPN
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ABSTRACT:
SUBMITTER: Meng Y
PROVIDER: S-EPMC10695992 | biostudies-literature | 2023 Nov
REPOSITORIES: biostudies-literature
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Project description:BackgroundN6-methyladenosine (m6A) methylation, a well-known modification with new epigenetic functions, has been reported to participate in the tumorigenesis of hepatocellular carcinoma (HCC), providing novel insights into the molecular pathogenesis of this disease. However, as the key component of m6A methylation, Wilms tumor 1-associated protein (WTAP) has not been well studied in HCC. Here we investigated the biological role and underlying mechanism of WTAP in liver cancer.MethodsWe determined the expression of WTAP and its correlation with clinicopathological features using tissue microarrays and the Cancer Genome Atlas (TCGA) dataset. And we clarified the effects of WTAP on HCC cells using cell proliferation assay, colony formation, Edu assay and subcutaneous xenograft experiments. We then applied RNA sequencing combined with gene expression omnibus (GEO) data to screen candidate targets of WTAP. Finally, we investigated the regulatory mechanism of WTAP in HCC by m6A dot blot assay, methylated RNA immunoprecipitation (MeRIP) assay, dual luciferase reporter assay, RNA immunoprecipitation (RIP) assay and Chromatin immunoprecipitation (ChIP) assay.ResultsWe demonstrated that WTAP was highly expressed in HCC which indicated the poor prognosis, and that WTAP expression served as an independent predictor of HCC survival. Functionally, WTAP promoted the proliferation capability and tumor growth of HCC cells in vitro and in vivo. Furthermore, ETS proto-oncogene 1 (ETS1) was identified as the downstream effector of WTAP. The m6A modification regulated by WTAP led to post-transcriptional suppression of ETS1, with the implication of Hu-Antigen R (HuR) as an RNA stabilizer. Then ETS1 was found to inhibit the progression of HCC and could rescue the phenotype induced by WTAP deficiency. Moreover, WTAP modulated the G2/M phase of HCC cells through a p21/p27-dependent pattern mediated by ETS1.ConclusionWe have identified that WTAP is significantly up-regulated in HCC and promotes liver cancer development. WTAP-guided m6A modification contributes to the progression of HCC via the HuR-ETS1-p21/p27 axis. Our study is the first to report that WTAP-mediated m6A methylation has a crucial role in HCC oncogenesis, and highlights WTAP as a potential therapeutic target of HCC treatment.
| S-EPMC6704583 | biostudies-literature
Project description:Linc-ROR have been well-demonstrated to play important roles in cancer progression and angiogenesis. However, the underlying oncogenic mechanism of Linc-ROR in hepatocellular carcinoma is poorly understood. In this study, we demonstrate that Linc-ROR plays an oncogenic role in part through its positive regulation of DEPDC1 expression. Mechanistically, Linc-ROR acts as competing endogenous RNA to stabilize DEPDC1 mRNA and regulates DEPDC1 mRNA stability by binding HNRNPK. Thus, these findings suggest that function of Linc-ROR-mediated DEPDC1 could predispose hepatocellular carcinoma patients to progression and angiogenesis, and may serve as a potential target for anticancer therapies.
| S-EPMC8571363 | biostudies-literature
Project description:PurposeN6-methyladenosine (m6A), the most abundant mRNA modification in mammals, is involved in various biological processes. KIAA1429 is an important methyltransferase participating in m6A modification. However, the role of KIAA1429 in hepatocellular carcinoma (HCC) is still not well understood. Here, we aimed to investigate the function of KIAA1429 and its corresponding regulation mechanisms in HCC.Patients and methodsHCC-related genes were analyzed by clinical and expression data of HCC patients in The Cancer Genome Atlas (TCGA) database. Expression of KIAA1429 was verified by quantitative reverse-transcription PCR, and interference efficiency was obtained using small interfering RNA (siRNA). Cell proliferation, migration, and invasion were assessed by cell counting kit-8 and transwell assays, and the m6A modification was detected by methylated RNA immunoprecipitation-PCR (MeRIP-PCR).ResultsWe found a difference in the expression of KIAA1429 between HCC and normal hepatic tissues by analyzing data from the TCGA database. Comparing HCC cell lines (HepG2, Huh-7, HepG2.2.15) with normal hepatic cells (HL-7702), we observed an identically significant difference in KIAA1429 expression. KIAA1429 significantly enhanced proliferation, migration, and invasion of HepG2 cells. Moreover, Kyoto Encyclopedia of Genes and Genomes functional enrichment analysis and correlation analysis revealed a significant negative correlation between KIAA1429 and ID2. In the subsequent MeRIP-PCR assay, downregulation of KIAA1429 inhibited m6A modification of ID2 mRNA.ConclusionKIAA1429 facilitated migration and invasion of HCC by inhibiting ID2 via upregulating m6A modification of ID2 mRNA.
| S-EPMC6510231 | biostudies-literature
Project description:Hepatocellular carcinoma (HCC), one of the most aggressive malignancies, ranks as the fourth leading cause of cancer-related deaths worldwide. Emerging evidence indicates that RNA N6-methyladenosine (m6A) plays a critical role in tumor progression. However, the biological function of YTHDF1 in HCC remains unclear. Here, we found that YTHDF1 expression was strikingly elevated in HCC tissues and cell lines and significantly associated with prognosis of HCC patients. Moreover, YTHDF1 expression was transcriptionally regulated by USF1 and c-MYC in HCC. Functional studies showed that YTHDF1 can promote HCC cell proliferation and metastasis both in vitro and in vivo. Multi-omics analysis revealed that YTHDF1 can accelerate the translational output of FZD5 mRNA in an m6A-dependent manner and function as an oncogene through the WNT/β-catenin pathway. Taken together, our study revealed an essential role of YTHDF1 in the progression of HCC cells, which indicated that targeting YTHDF1 may be a potential therapeutic strategy in HCC.
| S-EPMC7595883 | biostudies-literature
Project description:N6-methyladenosine (m6A), the most abundant internal modification in eukaryotic mRNA, plays important roles in many physiological and pathological processes, including the development and progression of cancer. RNA modification by m6A is regulated by methyltransferases, demethylases, and m6A-binding proteins that function in large part by regulating mRNA expression and function. Here, we investigate the expression of m6A regulatory proteins in breast cancer. We find that expression of KIAA1429/VIRMA, a component of the m6A methyltransferase complex, is upregulated in breast cancer tissue and correlates positively with poor survival. KIAA1429/VIRMA is mislocalized to the cytosol of breast cancer tissues and cell lines, and shRNA-mediated knockdown inhibits breast cancer cell proliferation, migration, and invasion. Mechanistically, KIAA1429/VIRMA is shown to bind to the m6A-dependent RNA binding protein insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), leading to recruitment and stabilization of m6A-modified hyaluronan synthase 2 (HAS2) mRNA. HAS2 mRNA and KIAA1429/VIRMA mRNA levels correlate positively in breast cancer tissues, suggesting that the KIAA1429/VIRMA-IGF2BP3-HAS2 axis promotes breast cancer growth and contributes to poor prognosis.
| S-SCDT-10_15252-EMBR_202255506 | biostudies-other
Project description:Abstract This study aimed to reveal the mechanism by which long noncoding RNAs (lncRNAs) modulate hepatocellular carcinoma (HCC) by regulating mRNA via the N6-methyladenosine (m6A) enzyme. The expression and clinical data of 365 HCC patients and 50 healthy control samples were downloaded from the the Cancer Genome Atlas (TCGA) database. Differentially expressed lncRNAs (DElncRNAs) and differentially expressed mRNAs (DEmRNAs) screened using limma packages from the R. m6A2Target database were used to predict the relationship between m6A enzyme-lncRNA and m6A enzyme-mRNA. The mRNAs in the lncRNA-m6A enzyme-mRNA network were subjected to enrichment analysis. Cox regression analysis was used to screen for RNAs significantly related to HCC prognosis. The expression of differentially expressed RNAs (DERs) was verified using the TCGA dataset and GSE55092. Eighty-five DElncRNAs and 747 DEmRNAs were identified. The mRNAs in the lncRNA-m6A enzyme-mRNA network were primarily involved in mitotic cell division, the p53 signaling pathway, and the cell cycle. Three lncRNAs and 14 mRNAs were significantly associated with HCC prognosis. Furthermore, the expression of 12 DERs differed significantly between patients in the early and advanced stages. LINC00665 was predicted to regulate 11 mRNAs by modulating IGF2BP1, IGF2BP2, and YTHDF1. Thus, this study provides new insights into the roles of lncRNA and m6A enzymes in HCC.
| S-EPMC8847717 | biostudies-literature
Project description:BackgroundN6-Methyladenosine (m6A) methylation, a common form of RNA modification, play an important role in the pathogenesis of various diseases and in the ontogeny of organisms. Nevertheless, the precise function of m6A methylation in photoaging remains unknown.ObjectivesThis study aims to investigate the biological role and underlying mechanism of m6A methylation in photoaging.Methodsm6A dot blot, Real-time quantitative PCR (RT-qPCR), western blot and immunohistochemical (IHC) assays were employed to detect the m6A level and specific m6A methylase in ultraviolet ray (UVR)-induced photoaging tissue. The profile of m6A-tagged mRNA was identified by methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA-seq analysis. Finally, we investigated the regulatory mechanism of KIAA1429 by MeRIP-qPCR, RNA knockdown and immunofluorescence assay.Resultsm6A levels were increased in photoaging and were closely associated with the upregulation of KIAA1429 expression. 1331 differentially m6A methylated genes were identified in the UVR group compared with the control group, of which 1192 (90%) were hypermethylated. Gene ontology analysis showed that genes with m6A hypermethylation and mRNA downregulation were mainly involved in extracellular matrix metabolism and collagen metabolism-related processes. Furthermore, KIAA1429 knockdown abolished the downregulation of TGF-bRII and upregulation of MMP1 in UVR-irradiated human dermal fibroblasts (HDFs). Mechanically, we identified MFAP4 as a target of KIAA1429-mediated m6A modification and KIAA1429 might suppress collagen synthesis through an m6A-MFAP4-mediated process.ConclusionsThe increased expression of KIAA1429 hinders collagen synthesis during UVR-induced photoaging, suggesting that KIAA1429 represents a potential candidate for targeted therapy to mitigate UVR-driven photoaging.
| S-EPMC11389345 | biostudies-literature
Project description:N6-methyladenosine (m6A) is capable of mediating circRNA generation in carcinoma biology. Nevertheless, the posttranscriptional systems of m6A and circRNA in hepatocellular carcinoma (HCC) development are still unclear. The present study identified a circRNA with m6A modification, circHPS5, which was increased in neoplasm HCC tissues and indicated poor patient survival. Silencing of circHPS5 inhibited epithelial-mesenchymal transition (EMT) and cancer stem-like cell (CSC) phenotypes. Notably, METTL3 could direct the formation of circHPS5, and specific m6A controlled the accumulation of circHPS5. YTHDC1 facilitated the cytoplasmic output of circHPS5 under m6A modification. In addition, we demonstrated that circHPS5 can act as a miR-370 sponge to regulate the expression of HMGA2 and further accelerate HCC cell tumorigenesis. Accordingly, the m6A modification of circHPS5 was found to modulate cytoplasmic output and increase HMGA2 expression to facilitate HCC development. The new regulatory model of "circHPS5-HMGA2" provides a new perspective for circHPS5 as an important prognostic marker and therapeutic target in HCC and provides mechanistic insight for exploring the carcinogenic mechanism of circHPS5 in HCC.
| S-EPMC8517093 | biostudies-literature
Project description:Increasing evidence supports that N6-methyladenine (m6A) and long noncoding RNAs (lncRNAs) both act as master regulators involved in breast cancer (BC) tumorigenesis at epigenetic modification level. Here, our research tries to unveil the interaction of m6A and lncRNAs on BC progression and explore the underlying regulatory mechanism. In the current study, we found that LINC00667 was m6A-modified lncRNA, which was up-regulated upon the overexpression of KIAA1429. The high expression of LINC00667 was correlated with the prognosis of BC patients. Bio-functional assays indicated that LINC00667 promoted the proliferation and migration of BC cells. Mechanistic assays illustrated that KIAA1429 targeted the m6A modification site of LINC00667 and enhanced its mRNA stability. Moreover, LINC00667 positively regulated the KIAA1429 via sponging miR-556-5p, forming a KIAA1429/m6A/LINC00667/miR-556-5p feedback loop. Collectively, the central findings of our study suggest that KIAA1429-induced LINC00667 exerted its functions as an oncogene in BC progression through m6A-dependent feedback loop.
| S-EPMC9275968 | biostudies-literature
Project description:Ezrin, one of the ezrin-radixin-moesin (ERM) proteins, is involved in the formation of cell membrane processes and has been implicated in the promotion of cancer proliferation and metastasis. However, the possible role of ezrin in hepatocellular carcinoma (HCC) metastasis and glycolysis reprogramming has remained unclear. In this study, we found that ezrin was upregulated in HCC tissues, and its overexpression was linked with HCC patients' aggressive tumor characteristics and poor prognosis. Functional experiments further revealed that ezrin overexpression promoted HCC cell proliferation, epithelial-to-mesenchymal transition (EMT) progression and angiogenesis. In addition, by measuring glucose consumption, lactate production, ATP levels and the expression of glucose metabolism-related markers in HCC cells, we investigated whether ezrin regulated glucose metabolism. Moreover, 2-deoxy-D-glucose (2-DG) affected ezrin-mediated proliferation, migration and EMT of HCC cells, which suggested that ezrin may, at least in part, promote HCC progression by regulating glycolysis reprogramming. Based on our results, we proposed that ezrin was involved in HCC progression and may be a valid prognostic marker.
| S-EPMC7648033 | biostudies-literature