Therapeutic Target In Human Cancer Research Articles

Discovery of Potent and Selective G9a Degraders for the Treatment of Pancreatic Cancer.

G9a, which was initially identified as a histone H3 Lys9 (H3K9) methyltransferase, is potentially an attractive therapeutic target for human cancers. Despite its importance, there is no available selective G9a chemical probe because its homologous protein GLP shares approximately 80% of its sequence with G9a. The development of G9a chemical probes with high selectivity for G9a over GLP is a big challenge but is extremely valuable for understanding G9a-related biology. Herein, we developed a first-in-class selective G9a degrader G9D-4, which induced a dose- and time-dependent G9a degradation without degradation of GLP. G9D-4 exhibited effective antiproliferative activities in a panel of pancreatic cancer cell lines and was able to sensitize KRASG12D mutant pancreatic cancer cells to KRASG12D inhibitor MRTX1133. These data clearly demonstrated the practicality and importance of a selective G9a degrader as a preliminary chemical probe suitable for understanding G9a-related biology and a promising strategy for the treatment of pancreatic cancer.

Integrated Bioinformatics Analysis and Transcriptomics Analysis Predict Jumonji and AT Rich Interacting Domain2 (JARID2) as a Therapeutic Target in Human Cancers

Integrated Bioinformatics Analysis and Transcriptomics Analysis Predict Jumonji and AT Rich Interacting Domain2 (JARID2) as a Therapeutic Target in Human Cancers

Pan-cancer analysis combined with experiments predicts NNMT as a therapeutic target for human cancers

The identification of effective therapeutic targets plays a pivotal role in advancing cancer treatment outcomes. We employed a comprehensive pan-cancer analysis, complemented by experimental validation, to explore the potential of Nicotinamide N-methyltransferase (NNMT) as a promising therapeutic strategy for human cancers. By analyzing large-scale transcriptomic datasets across various cancer types, we consistently observed upregulated expression of NNMT. Furthermore, elevated NNMT expression correlated with inferior overall survival in multiple cancer cohorts, underscoring its significance as a prognostic biomarker. Additionally, we investigated the relationship between NNMT expression and the tumor immune microenvironment, which plays a crucial role in regulating anti-tumor immune responses. To confirm the malignant functions of NNMT in tumor cells, we conducted a series of cell-based experiments, revealing that NNMT promotes cancer cell proliferation and invasion, indicative of its oncogenic properties. The integration of computational analysis and experimental validation in our study firmly establishes NNMT as a potential therapeutic target for human cancers. Specifically, targeting NNMT holds promise for the development of innovative and effective cancer treatments. Further investigations into NNMT's role in cancer pathogenesis could potentially pave the way for groundbreaking advancements in cancer treatment.

LncRNA TUG1 and its Molecular Mechanisms in Human Cancer.

As lncRNAs have increasingly been investigated, they are no longer simply defined as RNAs with no transcription capability. Studies have identified significant associations between the abnormal expression of lncRNAs and human diseases, particularly the mechanisms by which lncRNAs play a part in cancers, which are of considerable attention to researchers. As a result of the complex spatial structure, the mechanisms of interaction of lncRNAs in cancer cells are also complicated and diversified. Among a series of lncRNAs, TUG1, which is now considered to be a very high-value lncRNA, has recently been identified to express abnormally in some malignancies, leading to different alterations in cancer cells proliferation, migration, invasion, apoptosis, and drug resistance, and hence promoting or inhibiting cancer progression. Current studies have implicitly indicated that TUG1 can be used as a therapeutic target for human cancers. However, the biological functions of TUG1 have been studied for a short period of time, and the complete molecular mechanism still needs to be clarified. Accordingly, this review focuses on the principal molecular mechanisms of TUG1 in human cancers and the specific mechanisms of action in different cancer development processes based on existing studies.

Frizzled receptors (FZDs) in Wnt signaling: potential therapeutic targets for human cancers.

Frizzled receptors (FZDs) are key contributors intrinsic to the Wnt signaling pathway, activation of FZDs triggering the Wnt signaling cascade is frequently observed in human tumors and intimately associated with an aggressive carcinoma phenotype. It has been shown that the abnormal expression of FZD receptors contributes to the manifestation of malignant characteristics in human tumors such as enhanced cell proliferation, metastasis, chemotherapy resistance as well as the acquisition of cancer stemness. Given the essential roles of FZD receptors in the Wnt signaling in human tumors, this review aims to consolidate the prevailing knowledge on the specific status of FZD receptors (FZD1-10) and elucidate their respective functions in tumor progression. Furthermore, we delineate the structural basis for binding of FZD and its co-receptors to Wnt, and provide a better theoretical foundation for subsequent studies on related mechanisms. Finally, we describe the existing biological classes of small molecule-based FZD inhibitors in detail in the hope that they can provide useful assistance for design and development of novel drug candidates targeted FZDs.

Abstract 5912: Rational design of a small-molecule inhibitor targeting the allosteric site of sos1 in oncogenic k-ras pancreatic cancer

Abstract Oncogenic Kras signaling is a key therapeutic target in human cancers. Ras activation is catalyzed by guanine nucleotide exchange factors (GEFs), of which SOS1 is a major player that transduces receptor tyrosine kinase signaling to Ras. In addition to recently devised oncogenic Kras targeting small molecule inhibitors, disrupting the catalytic interaction between Ras and SOS1 has emerged as an attractive therapeutic strategy in working synergistically with Kras inhibitors and overcoming resistance. Previous studies have demonstrated an active “feed forward” loop of active Kras binding to the allosteric site of SOS1 that further stimulates SOS1 catalytic activation of wild type H/N/Kras, which is required for oncogenic Kras driven tumorigenesis. Here we have developed a rational approach that combines virtual screening with experimental screening to identify small molecule inhibitors that target the allosteric site of SOS1 to suppress oncogenic Kras mediated SOS1-regulated wild-type Ras activities. Unlike SOS1 catalytic site inhibitors which can have significant toxicity due to their ability to inhibit normal Ras signaling function, the lead SOS1 allosteric inhibitors developed in our laboratory binds to the allosteric site of SOS1 and blocks active Ras interaction with SOS1: we found these inhibitors can competitively suppresses SOS1-Ras interaction at the SOS1 allosteric site and dose-dependently inhibits the feed-forward SOS1 GEF activity. Mutagenesis and structure-activity relationship studies mapped the site of action to the SOS1 allosteric site, and preliminarily defined the chemical moieties in the inhibitor essential for the activity. The inhibitor showed dose-dependent and selective efficacy in inhibiting WT Ras activity, downstream signaling activities, and associated cell proliferation in KRAS mutation cells but not KRAS wild-type cells. Compared to the SOS1 catalytic inhibitor, BI3406, our inhibitors showed better selectivity for KRAS mutant pancreatic cancer cells vs. WT KRAS cells. These studies establish a proof of principle for the rational design of small molecule inhibitors targeting an oncogenic Kras specific allosteric site of SOS1 and provide a novel therapeutic concept to target KRAS-driven tumors more effectively. Citation Format: Xin Duan, Chris R Evelyn, Jacek Biesiada, James F Johnson, William L. Seibel, Jaroslaw Meller, Yi Zheng. Rational design of a small-molecule inhibitor targeting the allosteric site of sos1 in oncogenic k-ras pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5912.

Pan-cancer integrated analysis of ANKRD1 expression, prognostic value, and potential implications in cancer

There is substantial evidence demonstrating the crucial role of inflammation in oncogenesis. ANKRD1 has been identified as an anti-inflammatory factor and is related to tumor drug resistance. However, there have been no studies investigating the prognostic value and molecular function of ANKRD1 in pan-cancer. In this study, we utilized the TCGA, GTEx, GSCALite, ENCORI, CTRP, DAVID, AmiGO 2, and KEGG databases as well as R language, to explore and visualize the role of ANKRD1 in tumors. We employed the ROC curve to explore its diagnostic significance, while the Kaplan–Meier survival curve and Cox regression analysis were used to investigate its prognostic value. Additionally, we performed Pearson correlation analysis to evaluate the association between ANKRD1 expression and DNA methylation, immune cell infiltration, immune checkpoints, TMB, MSI, MMR, and GSVA. Our findings indicate that ANKRD1 expression is dysregulated in pan-cancer. The ROC curve revealed that ANKRD1 expression is highly sensitive and specific in diagnosing CHOL, LUAD, LUSC, PAAD, SKCM, and UCS (AUC > 85.0%, P < 0.001). Higher ANKRD1 expression was related to higher overall survival (OS) in LGG, but with lower OS in COAD and STAD (P < 0.001). Moreover, Cox regression and nomogram analyzes suggested that ANKRD1 is an independent factor for COAD, GBM, HNSC, and LUSC. Dysregulation of ANKRD1 expression in pan-cancer involves DNA methylation and microRNA regulation. Using the CTRP database, we discovered that ANKRD1 may influence the half-maximal inhibitory concentration (IC50) of several anti-tumor drugs. ANKRD1 expression showed significant correlations with immune cell infiltration (including cancer-associated fibroblast and M2 macrophages), immune checkpoints, TMB, MSI, and MMR. Furthermore, ANKRD1 is involved in various inflammatory and immune pathways in COAD, GBM, and LUSC, as well as cardiac functions in HNSC. In vitro experiments demonstrated that ANKRD1 promotes migration, and invasion activity, while inhibiting apoptosis in colorectal cancer cell lines (Caco2, SW480). In summary, ANKRD1 represents a potential prognostic biomarker and therapeutic target in human cancers, particularly in COAD.

The interaction between lncRNAs and transcription factors regulating autophagy in human cancers: A comprehensive and therapeutical survey.

Autophagy, as a highly conserved cellular process, participates in cellular homeostasis by degradation and recycling of damaged organelles and proteins. Besides, autophagy has been evidenced to play a dual role through cancer initiation and progression. In the early stage, it may have a tumor-suppressive function through inducing apoptosis and removing damaged cells and organelles. However, late stages promote tumor progression by maintaining stemness features and induction of chemoresistance. Therefore, identifying and targeting molecular mechanisms involved in autophagy is a potential therapeutic strategy for human cancers. Multiple transcription factors (TFs) are involved in the regulation of autophagy by modulating the expression of autophagy-related genes (ATGs). In addition, a wide array of long noncoding RNAs (lncRNAs), a group of regulatory ncRNAs, have been evidenced to regulate the function of these autophagy-related TFs through tumorigenesis. Subsequently, the lncRNAs/TFs/ATGs axis shows great potential as a therapeutic target for human cancers. Therefore, this review aimed to summarize new findings about the role of lncRNAs in regulating autophagy-related TFs with therapeutic perspectives.

Discovery of Novel PROTAC Degraders of p300/CBP as Potential Therapeutics for Hepatocellular Carcinoma.

Adenoviral E1A binding protein 300 kDa (p300) and its closely related paralog CREB binding protein (CBP) are promising therapeutic targets for human cancer. Here, we report the first discovery of novel potent small-molecule PROTAC degraders of p300/CBP against hepatocellular carcinoma (HCC), one of the most common solid tumors. Based upon the clinical p300/CBP bromodomain inhibitor CCS1477, a conformational restriction strategy was used to optimize the linker to generate a series of PROTACs, culminating in the identification of QC-182. This compound effectively induces p300/CBP degradation in the SK-HEP-1 HCC cells in a dose-, time-, and ubiquitin-proteasome system-dependent manner. QC-182 significantly downregulates p300/CBP-associated transcriptome in HCC cells, leading to more potent cell growth inhibition compared to the parental inhibitors and the reported degrader dCBP-1. Notably, QC-182 potently depletes p300/CBP proteins in mouse SK-HEP-1 xenograft tumor tissue. QC-182 is a promising lead compound toward the development of p300/CBP-targeted HCC therapy.

Prognostic and immune roles of UROC1 in human cancers: from mechanism exploration of NAFLD and HCC to pan-cancer analysis.

Both non-alcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC) are prevalent diseases worldwide. This study aimed to explore the underlying mechanisms of NAFLD and HCC and identify new therapeutic targets for human cancers. NAFLD and HCC gene expression profiles were obtained from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) and weighted gene co-expression network analysis (WGCNA) were utilized to identify co-expressed genes associated with NAFLD and HCC. Public databases were consulted to find common targets of NAFLD and HCC. Enrichment analysis and CIBERSORT techniques were employed to analyze the pathways enriched with DEGs and the attributes of infiltrating immune cells. Furthermore, the expression data of UROC1 and clinical information of patients were acquired from The Cancer Genome Atlas (TCGA) database. Finally, the expression of the UROC1 was validated by immunohistochemistry (IHC). Through a comprehensive bioinformatics analysis, eight hub genes (CCL2, CCR2, IL6, CSF3R, ATL2, SESN3, UROC1, FIGNL1) were identified. Enrichment analysis indicated that inflammatory and immune response may be common features between NAFLD and HCC. CIBER-SORT analysis revealed an imbalance of plasma cells and macrophages in NAFLD and HCC. Pan-cancer analysis demonstrated that UROC1 expression was related to clinical outcomes and tumor immunity in various cancers. Moreover, a strong correlation was exhibited between UROC1 expression and crucial elements, including tumor mutation burden (TMB), microsatellite instability (MSI), multiple immune checkpoints (ICP), and tumor microenvironment (TME). Importantly, an adverse clinical prognosis of HCC was linked to decreased UROC1 expression, which was consistent with IHC results. We identified eight hub genes (CCL2, CCR2, IL6, CSF3R, ATL2, SESN3, UROC1, FIGNL1), which may become early diagnostic and therapeutic targets for NAFLD and HCC. The pan-cancer analysis of UROC1 provides new evidence for its broad application prospects in the field of HCC and other cancers.

Discovery of a potent and selective covalent threonine tyrosine kinase (TTK) inhibitor

Threonine tyrosine kinase (TTK) is a critical component of the spindle assembly checkpoint and plays a pivotal role in mitosis. TTK has been identified as a potential therapeutic target for human cancers. Here, we describe our design, synthesis and evaluation of a class of covalent TTK inhibitors, exemplified by 16 (SYL1073). Compound 16 potently inhibits TTK kinase with an IC50 of 0.016 μM and displays improved selectivity in a panel of kinases. Mass spectrometry analysis reveals that 16 covalently binds to the C604 cysteine residue in the hinge region of the TTK kinase domain. Furthermore, 16 achieves strong potency in inhibiting the growth of various human cancer cell lines, outperforming its relative reversible inhibitor, and eliciting robust downstream effects. Taken together, compound 16 provides a valuable lead compound for further optimization toward the development of drug for treatment of human cancers.

Serum LINC00152 and UCA1 in HCV-Induced Hepatocellular Carcinoma: Clinical Significance and Prognostic Value.

Despite significant advancements in the molecular characterization of hepatocellular carcinoma (HCC), no oncogene addiction has been discovered. Long noncoding RNAs (lncRNAs) have a lot of promise as cancer biomarkers. LINC00152 and UCA1 have shown potential as diagnostic, prognostic, and therapeutic targets for human cancers. To investigate the diagnostic and prognostic potential of serum LINC00152 and UCA1 in hepatocellular carcinoma (HCC). The expression levels of LINC00152 and UCA1 in blood samples from 120 patients (60 with HCC, 60 with liver cirrhosis) and 40 healthy subjects were assessed using real-time qRT-PCR. Serum LINC00152 and UCA1 expression were considerably higher in HCC patients compared to patients with liver cirrhosis and the healthy controls (p<0.001 and p<0.001 respectively). And their expressions in the liver cirrhosis group were significantly higher than in healthy controls. Both lncRNAs performed well in the ROC analysis, distinguishing HCC patients from patients with liver cirrhosis. Higher levels of LINC00152 expression were linked to lesions in both lobes of the liver (p=0.02), while higher levels of UCA1 expression were linked to vascular invasion and the late stage (p=0.01, p=0.03 respectively). The multivariate analysis showed that a high level of LINC00152 in the blood was an independent indicator of a bad outcome for HCC patients (HR=2.23, 95% CI= 1.30-5.29, p=0.03). Serum LINC00152 and UCA1 expression were upregulated in patients with HCC, suggesting their use as non-invasive biomarkers for HCC. Furthermore, LINC00152 has the potential to serve as a prognostic indicator.

Comprehensive analysis of TLX2 in pan cancer as a prognostic and immunologic biomarker and validation in ovarian cancer

T cell leukemia homeobox 2 (TLX2) plays an important role in some tumors. Bioinformatics and experimental validation represent a useful way to explore the mechanisms and functions of TLX2 gene in the cancer disease process from a pan cancer perspective. TLX2 was aberrantly expressed in pan cancer and cell lines and correlated with clinical stage. High TLX2 expression was significantly associated with poor overall survival in COAD, KIRC, OC, and UCS. The greatest frequency of TLX2 alterations in pan cancer was amplification. Alterations of NXF2B, MSLNL, PCGF1, INO80B-WBP1, LBX2-AS1, MRPL53, LBX2, TTC31, WDR54, and WBP1 co-occurred in the TLX2 alteration group. PFS was significantly shorter in the TLX2-altered group (n = 6) compared to the TLX2-unaltered group (n = 400). Methylation levels of TLX2 were high in 17 tumors. TLX2 expression was associated with MSI in seven tumors and TMB in five tumors. TLX2 expression was associated with immune infiltration and immune checkpoint genes. TLX2 may be associated with some pathways and chemoresistance. We constructed a possible competing endogenous RNA (ceRNA) network of LINC01010/miR-146a-5p/TLX2 in OC. TLX2 expression was significantly upregulated in ovarian cancer cell lines compared to ovarian epithelial cell lines. Aberrant expression of TLX2 in pan cancer may promote tumorigenesis and progression through different mechanisms. TLX2 may represent an important therapeutic target for human cancers.

Dual inhibition of CDK12 and CDK13 uncovers actionable vulnerabilities in patient-derived ovarian cancer organoids

BackgroundHigh grade serous ovarian cancer (HGSOC) is highly lethal, partly due to chemotherapy resistance and limited availability of targeted approaches. Cyclin dependent kinases 12 and 13 (CDK12/13) are promising therapeutic targets in human cancers, including HGSOC. Nevertheless, the effects of their inhibition in HGSOC and the potential synergy with other drugs are poorly known.MethodsWe analyzed the effects of the CDK12/13 inhibitor THZ531 in HGSOC cells and patient-derived organoids (PDOs). RNA sequencing and quantitative PCR analyses were performed to identify the genome-wide effects of short-term CDK12/13 inhibition on the transcriptome of HGSOC cells. Viability assays with HGSOC cells and PDOs were performed to assess the efficacy of THZ531 as single agent or in combination with clinically relevant drugs.ResultsThe CDK12 and CDK13 genes are deregulated in HGSOC and their concomitant up-regulation with the oncogene MYC predicts poor prognosis. HGSOC cells and PDOs display high sensitivity to CDK12/13 inhibition, which synergizes with drugs in clinical use for HGSOC. Transcriptome analyses revealed cancer-relevant genes whose expression is repressed by dual CDK12/13 inhibition through impaired splicing. Combined treatment with THZ531 and inhibitors of pathways regulated by these cancer relevant genes (EGFR, RPTOR, ATRIP) exerted synergic effects on HGSOC PDO viability.ConclusionsCDK12 and CDK13 represent valuable therapeutic targets for HGSOC. We uncovered a wide spectrum of CDK12/13 targets as potential therapeutic vulnerabilities for HGSOC. Moreover, our study indicates that CDK12/13 inhibition enhances the efficacy of approved drugs that are already in use for HGSOC or other human cancers.

Oncogenic roles and related mechanisms of the long non-coding RNA MINCR in human cancers.

Long non-coding RNAs (lncRNAs) play vital roles in regulating epigenetic mechanisms and gene expression levels, and their dysregulation is closely associated with a variety of diseases such as cancer. Several studies have demonstrated that lncRNAs are dysregulated during tumor progression. Recently, the MYC-induced long non-coding RNA MINCR, a newly identified lncRNA, has been demonstrated to act as an oncogene in different cancers, including gallbladder cancer, hepatocellular cancer, colorectal cancer, non-small cell lung cancer, oral squamous cell carcinoma, nasopharyngeal cancer, and glioma. Moreover, MINCR has been reported to act as a biomarker in the prognosis of patients with different cancers. In this review, we summarize and analyze the oncogenic roles of MINCR in a variety of human cancers in terms of its clinical significance, biological functions, cellular activities, and regulatory mechanism. Our analysis of the literature suggests that MINCR has potential as a novel biomarker and therapeutic target in human cancers.

NALCN is a potential biomarker and therapeutic target in human cancers.

Background: Sodium leak channel non-selective (NALCN), known as a voltage-independent Na+ channel, is increasingly considered to play vital roles in tumorigenesis and metastasis of human cancers. However, no comprehensive pan-cancer analysis of NALCN has been conducted. Our study aims to explore the potential diagnostic, prognostic and therapeutic value of NALCN in human cancers. Methods: Through comprehensive application of datasets from Human Protein Atlas (HPA), The Cancer Genome Atlas (TCGA), Cancer Cell Line Encyclopedia (CCLE), Enhanced Version of Tumor Immune Estimation Resource (TIMER2.0), Tumor and Immune System Interaction Database (TISIDB), The University of Alabama at Birmingham Cancer data analysis Portal (UALCAN), cBioPortal, GeneMANIA and Search Tool for the Retrieval of Interaction Gene/Proteins (STRING) databases, we explored the potential roles of NALCN in different cancers. The differential expression, prognostic implications, pathological stages and grades, molecular and immune subtypes, diagnostic accuracy, tumor mutation burden (TMB), microsatellite instability (MSI), mismatch repair (MMR) genes, immune checkpoint genes, chemokine genes, major histocompatibility complex (MHC)-related genes, tumor-infiltrating immune cells (TIICs), promoter methylation, mutations, copy number alteration (CNA), and functional enrichment related to NALCN were analyzed. Results: Most cancers lowly expressed NALCN. Upregulated NALCN expression was associated with poor or better prognosis in different cancers. Moreover, NALCN was correlated with clinicopathological features in multiple cancers. NALCN showed high diagnostic accuracy in 5 caner types. NALCN is highly linked with immune-related biomarkers, immune-related genes and TIICs. Significant methylation changes and genetic alteration of NALCN can be observed in many cancers. Enrichment analysis showed that NALCN is closely related to multiple tumor-related signaling pathways. Conclusion: Our study revealed the vital involvement of NALCN in cancer. NALCN can be used as a prognostic biomarker for immune infiltration and clinical outcomes, and has potential diagnostic and therapeutic implications.

Diverse Functions of MiR-425 in Human Cancer.

miRNAs are a type of small endogenous noncoding RNA composed of 20-22 nucleotides that can regulate gene expression by targeting the 3' untranslated region of mRNA. Many investigations have discovered that miRNAs have a role in the development and progression of human cancer. Several aspects of tumor development are affected by miR-425, including growth, apoptosis, invasion, migration, epithelial-mesenchymal transition, and drug resistance. In this article, we discuss the properties and research development of miR-425, focusing on the regulation and function of miR-425 in various cancers. Furthermore, we discuss the clinical implications of miR-425. This review may broaden our horizon for better understanding the role of miR-425 as biomarkers and therapeutic targets in human cancer.

Discovery of a Potent and Selective STAT5 PROTAC Degrader with Strong Antitumor Activity In Vivo in Acute Myeloid Leukemia.

STAT5 is an attractive therapeutic target for human cancers. We report herein the discovery of a potent and selective STAT5 degrader with strong antitumor activity in vivo. We first obtained small-molecule ligands with sub-micromolar to low micromolar binding affinities to STAT5 and STAT6 SH2 domains and determined co-crystal structures of three such ligands in complex with STAT5A. We successfully transformed these ligands into potent and selective STAT5 degraders using the PROTAC technology with AK-2292 as the best compound. AK-2292 effectively induces degradation of STAT5A, STAT5B, and phosphorylated STAT5 proteins in a concentration- and time-dependent manner in acute myeloid leukemia (AML) cell lines and demonstrates excellent degradation selectivity for STAT5 over all other STAT members. It exerts potent and specific cell growth inhibitory activity in AML cell lines with high levels of phosphorylated STAT5. AK-2292 effectively reduces STAT5 protein in vivo and achieves strong antitumor activity in mice at well-tolerated dose schedules.

Pan-cancer analysis reveals NAA50 as a cancer prognosis and immune infiltration-related biomarker.

Background: N-Alpha-Acetyltransferase 50 (NAA50) has acetyltransferase activity and is important for chromosome segregation. However, the function and mechanism of NAA50 expression in cancer development was still unclear. Here, we systematically researched the function and mechanism of NAA50 in pan-cancer, and further verified the results of NAA50 in lung adenocarcinoma (LUAD). Methods: In this study, using the online databases TIMER2.0, SangerBox3.0, HPA, UCSC, GEPIA, cBioPortal, UALCAN, TISIDB, CancerSEA and LinkedOmics, we focused on the relevance between NAA50 and oncogenesis, progression, methylation, immune infiltration, function and prognosis. In addition, the proliferation of cells was detected by CCK-8 and Edu assay. Finally, we analyzed the relationship between the expression of NAA50 and cell cycle related proteins. Results: Pan-cancer analysis indicated that NAA50 was overexpressed in most cancers. And there was a significant correlation between NAA50 expression and the prognosis of cancer patients. In the meantime, NAA50 gene changes occur in a variety of tumors. Compared with normal tissues, the methylation level of NAA50 promoter increased in most cancer tissues. In addition, the results exhibited that in most cancers, NAA50 was significantly positively correlated with bone myeloid-derived suppressor cell (MDSC) infiltration and negatively correlated with T cell NK infiltration. Moreover, functional enrichment indicated that NAA50 regulates cell cycle and proliferation in LUAD. In vitro experiments testified that knockout of NAA50 could significantly inhibit the proliferation of LUAD. Conclusion: NAA50 may be a potential biomarker and oncogene of pan-cancer, especially LUAD, which may promote the occurrence and development of tumors through different mechanisms. Furthermore, NAA50 was bound up with to immune cell infiltration in pan-cancer, meaning NAA50 may be an important therapeutic target for human cancers.

The m6A reader IGF2BP2 regulates glutamine metabolism and represents a therapeutic target in acute myeloid leukemia.

N6-Methyladenosine (m6A) modification and its modulators play critical roles and show promise as therapeutic targets in human cancers, including acute myeloid leukemia (AML). IGF2BP2 was recently reported as an m6A binding protein that enhances mRNA stability and translation. However, its function in AML remains largely elusive. Here we report the oncogenic role and the therapeutic targeting of IGF2BP2 in AML. High expression of IGF2BP2 is observed in AML and associates with unfavorable prognosis. IGF2BP2 promotes AML development and self-renewal of leukemia stem/initiation cells by regulating expression of critical targets (e.g., MYC, GPT2, and SLC1A5) in the glutamine metabolism pathways in an m6A-dependent manner. Inhibiting IGF2BP2 with our recently identified small-molecule compound (CWI1-2) shows promising anti-leukemia effects invitro and invivo. Collectively, our results reveal a role of IGF2BP2 and m6A modification in amino acid metabolism and highlight the potential of targeting IGF2BP2 as a promising therapeutic strategy in AML.