Endogenous transmembrane protein UT2 inhibits pSTAT3 and suppresses hematological malignancy

Lee, Dongjun; Wang, Yinghua; Kalaitzidis, Demetrios; Ramachandran, Janani; Eda, Homare; Sykes, David B.; Raje, Noopur; Scadden, David T.

doi:10.1172/jci84620

Cited by 12 publications

(11 citation statements)

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“…ARMH4 , also named C14ORF37 , encodes a protein that contains an armadillo-like helical domain. It has been shown that ARMH4 can interact with and inhibit the function of mTOR complex 2 kinase activity and function as a tumor suppressor in hematological malignancies, which is driven by interleukin 6 (IL-6)–signal transducer and activator of transcription 3 (STAT3) signaling pathways ( 51 , 52 ). Wang et al.…”

Section: Discussionmentioning

confidence: 99%

Identification of Hub Genes Associated With Clear Cell Renal Cell Carcinoma by Integrated Bioinformatics Analysis

et al. 2021

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BackgroundClear cell renal cell carcinoma (ccRCC) is a common genitourinary cancer type with a high mortality rate. Due to a diverse range of biochemical alterations and a high level of tumor heterogeneity, it is crucial to select highly validated prognostic biomarkers to be able to identify subtypes of ccRCC early and apply precision medicine approaches.MethodsTranscriptome data of ccRCC and clinical traits of patients were obtained from the GSE126964 dataset of Gene Expression Omnibus and The Cancer Genome Atlas Kidney Renal Clear Cell Carcinoma (TCGA-KIRC) database. Weighted gene co-expression network analysis (WGCNA) and differentially expressed gene (DEG) screening were applied to detect common differentially co-expressed genes. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes analysis, survival analysis, prognostic model establishment, and gene set enrichment analysis were also performed. Immunohistochemical analysis results of the expression levels of prognostic genes were obtained from The Human Protein Atlas. Single-gene RNA sequencing data were obtained from the GSE131685 and GSE171306 datasets.ResultsIn the present study, a total of 2,492 DEGs identified between ccRCC and healthy controls were filtered, revealing 1,300 upregulated genes and 1,192 downregulated genes. Using WGCNA, the turquoise module was identified to be closely associated with ccRCC. Hub genes were identified using the maximal clique centrality algorithm. After having intersected the hub genes and the DEGs in GSE126964 and TCGA-KIRC dataset, and after performing univariate, least absolute shrinkage and selection operator, and multivariate Cox regression analyses, ALDOB, EFHD1, and ESRRG were identified as significant prognostic factors in patients diagnosed with ccRCC. Single-gene RNA sequencing analysis revealed the expression profile of ALDOB, EFHD1, and ESRRG in different cell types of ccRCC.ConclusionsThe present results demonstrated that ALDOB, EFHD1, and ESRRG may act as potential targets for medical therapy and could serve as diagnostic biomarkers for ccRCC.

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Section: Discussionmentioning

confidence: 99%

Identification of Hub Genes Associated With Clear Cell Renal Cell Carcinoma by Integrated Bioinformatics Analysis

et al. 2021

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“…From the RNA-seq data for the TMZ-resistant LN18 GBM cells ( Figure 4 ), when comparing combined TMZ + OKN to UT treatments ( Figure 4 A ), interesting downregulated genes include DPT-TRAMP that enhances TGF-β1 activity, FOXO6 (elevated expression correlates with progression and prognosis in gastric cancer [40] ), COL3A1 (overexpression associated with bladder tumor progression [41] ), BGN (plays a role in enhancing vessel formation and tumor cell migration [42] ), and VAV3 (implicated in pancreatic cancer development [43] ), and interesting upregulated genes include NFKBIZ (promotes apoptosis [44] ), SOD2 (superoxide dismutase antioxidant [45] ), and ASNS (responsive to cellular stress [46] ). When comparing combined TMZ + OKN treatment to TMZ alone ( Figure 4 B ), interesting upregulated genes are RNF149 (stress sensor gene that amplifies p53 response to arrest cell cycle [47] ), IDO-1 (involved in human gliomas [48] ), and SLC14a2 (endogenous transmembrane protein upstream-of-mTORC2 (UT2) negatively regulates activation of STAT3 [49] ). Interesting downregulated genes include SUMO2 (overexpression of SUMO in conditions such as brain ischemia and hypoxia could increase cell survival, whereas the knockdown of SUMO expression has proven to be toxic to cells and associated with TGFβ1 in resistant glioma cells) [50] , HIST1H1C/H1.2 (knockdown of histone HIST1H1C inhibits high glucose–induced inflammation and cell toxicity [51] ), and PFN1 (profiling-1 phosphorylation is associated with tumor aggressiveness in human glioma) [52] .…”

Section: Discussionmentioning

confidence: 99%

OKN-007 Increases temozolomide (TMZ) Sensitivity and Suppresses TMZ-Resistant Glioblastoma (GBM) Tumor Growth

Towner

Smith

Saunders

et al. 2019

Translational Oncology

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Treatment of glioblastoma (GBM) remains a challenge using conventional chemotherapy, such as temozolomide (TMZ), and is often ineffective as a result of drug resistance. We have assessed a novel nitrone-based agent, OKN-007, and found it to be effective in decreasing tumor volumes and increasing survival in orthotopic GBM xenografts by decreasing cell proliferation and angiogenesis and increasing apoptosis. In this study, we assessed combining OKN-007 with TMZ in vivo in a human G55 GBM orthotopic xenograft model and in vitro in TMZ-resistant and TMZ-sensitive human GBM cell lines. For the in vivo studies, magnetic resonance imaging was used to assess tumor growth and vascular alterations. Percent animal survival was also determined. For the in vitro studies, cell growth, IC50 values, RNA-seq, RT-PCR, and ELISA were used to assess growth inhibition, possible mechanism-of actions (MOAs) associated with combined OKN-007 + TMZ versus TMZ alone, and gene and protein expression levels, respectively. Microarray analysis of OKN-007–treated rat F98 glioma tumors was also carried out to determine possible MOAs of OKN-007 in glioma-bearing animals either treated or not treated with OKN-007. OKN-007 seems to elicit its effect on GBM tumors via inhibition of tumorigenic TGF-β1, which affects the extracellular matrix. When combined with TMZ, OKN-007 significantly increases percent survival, decreases tumor volumes, and normalizes tumor blood vasculature in vivo compared to untreated tumors and seems to affect TMZ-resistant GBM cells possibly via IDO-1, SUMO2, and PFN1 in vitro. Combined OKN-007 + TMZ may be a potentially potent treatment strategy for GBM patients.

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“…Protein extracts were separated in 10% SDS-PAGE and electrotransferred to PVDF membranes (Immobilon-P; EMD Millipore). Antibodies used were as follows: MYC #ab32 (Abcam, Cambridge, USA) [ 56 ], #sc764 (Santa Cruz Biotechnology, USA) [ 57 ]; DNMT3B #ab122932 (Abcam, Cambridge, USA) [ 58 ],#nb100-56514 (Novus Biologicals, USA) [ 59 ]; TUBULIN #ab6046 (Abcam, Cambridge, USA) [ 22 ]; β-ACTIN #A5441 (Sigma-Aldrich, USA); GAPDH #sc25778 (Santa Cruz Biotechnology, USA) [ 60 ]; Anti-MOUSE HRP #31430 (Thermo Fisher, USA) [ 61 ]; Anti-RABBIT HRP #31460 (Thermo Fisher, USA) [ 62 ]. Protein quantitation was performed using ImageJ software ( https://imagej.nih.gov/ij/ ) [ 63 ].…”

Section: Methodsmentioning

confidence: 99%

DNMT3B overexpression contributes to aberrant DNA methylation and MYC-driven tumor maintenance in T-ALL and Burkitt’s lymphoma

et al. 2017

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Aberrant DNA methylation is a hallmark of cancer. However, our understanding of how tumor cell-specific DNA methylation patterns are established and maintained is limited. Here, we report that in T-cell acute lymphoblastic leukemia (T-ALL) and Burkitt’s lymphoma the MYC oncogene causes overexpression of DNA methyltransferase (DNMT) 1 and 3B, which contributes to tumor maintenance. By utilizing a tetracycline-regulated MYC transgene in a mouse T-ALL (EμSRα-tTA;tet-o-MYC) and human Burkitt’s lymphoma (P493-6) model, we demonstrated that DNMT1 and DNMT3B expression depend on high MYC levels, and that their transcription decreased upon MYC-inactivation. Chromatin immunoprecipitation indicated that MYC binds to the DNMT1 and DNMT3B promoters, implicating a direct transcriptional regulation. Hence, shRNA-mediated knock-down of endogenous MYC in human T-ALL and Burkitt’s lymphoma cell lines downregulated DNMT3B expression. Knock-down and pharmacologic inhibition of DNMT3B in T-ALL reduced cell proliferation associated with genome-wide changes in DNA methylation, indicating a tumor promoter function during tumor maintenance. We provide novel evidence that MYC directly deregulates the expression of both de novo and maintenance DNMTs, showing that MYC controls DNA methylation in a genome-wide fashion. Our finding that a coordinated interplay between the components of the DNA methylating machinery contributes to MYC-driven tumor maintenance highlights the potential of specific DNMTs for targeted therapies.

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Endogenous transmembrane protein UT2 inhibits pSTAT3 and suppresses hematological malignancy

Cited by 12 publications

References 95 publications

Identification of Hub Genes Associated With Clear Cell Renal Cell Carcinoma by Integrated Bioinformatics Analysis

Identification of Hub Genes Associated With Clear Cell Renal Cell Carcinoma by Integrated Bioinformatics Analysis

OKN-007 Increases temozolomide (TMZ) Sensitivity and Suppresses TMZ-Resistant Glioblastoma (GBM) Tumor Growth

DNMT3B overexpression contributes to aberrant DNA methylation and MYC-driven tumor maintenance in T-ALL and Burkitt’s lymphoma

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