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Deletion of Glutathione S-Transferase Omega 1 Activates Type I Interferon Genes and Downregulates Tissue Factor

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Deletion of Glutathione S-Transferase Omega 1 Activates Type I Interferon Genes and Downregulates Tissue Factor Published OnlineFirst June 22, 2020; DOI: 10.1158/0008-5472.CAN-20-0530 CANCER RESEARCH | TUMOR BIOLOGY AND IMMUNOLOGY Deletion of Glutathione S-Transferase Omega 1 Activates Type I Interferon Genes and Downregulates Tissue Factor A C Yibin Xu1,2, Armand Bankhead III2,3, Xiaoli Tian1,2, Jianming Tang1,2, Mats Ljungman2,4,5, and Nouri Neamati1,2 ABSTRACT ◥ GST omega 1 (GSTO1) is an atypical GST isoform that is tion of GSTO1. Transcription and protein expression of tissue overexpressed in several cancers and has been implicated in drug factor (gene name, F3) were downregulated in response to resistance. Currently, no small-molecule drug targeting GSTO1 is GSTO1 KO. F3 is associated with poor patient survival and under clinical development. Here we have validated GSTO1 as an promotion of tumor progression in multiple cancers and is a impactful target in oncology. Transcriptional profiling coupled known risk factor for metastasis. Transcription of F3 was reg- with proteomics uncovered novel pharmacodynamic markers ulated by IL1b, whose secretion decreased upon inhibition of and cellular pathways regulated by GSTO1. CRISPR/Cas9 GSTO1, suggesting that IL1b links GSTO1 expression and F3 GSTO1 knockout (KO) cell lines failed to form tumors or transcription. In summary, our results implicate GSTO1 as a displayed growth delay in vivo; they also formed smaller 3D potential therapeutic target in cancer and offer new mechanistic spheroids in vitro. Multiomics analysis in GSTO1 KO cells found insights into its significant role in cancer progression. a strong positive correlation with cell adhesion molecules and IFN response pathways and a strong negative correlation with Significance: These findings validate GSTO1 as a therapeutic Myc transcriptional signature. In addition, several clinically used target in cancer and implicate GSTO1 in the modulation of tumor drugs showed significant synthetic lethality with loss or inhibi- growth, immune responses, and expression of F3. Introduction associated with drug resistance (8, 9), and GSTO1 inhibitors have shown to sensitize cancer cell to cisplatin (5, 10). GSTO1 expression GST omega 1 (GSTO1), a member of the cytosolic GST family, is is also induced by chemotherapy and its knockdown halts breast cancer widely expressed in human tissues (1). GSTs are important detoxifying stem cell enrichment (11). Knockdown of GSTO1 leads to cell apoptosis enzymes that catalyze the conjugation of electrophilic substrates to in colorectal (5) and erythroleukemia cell lines (12) and causes signif- glutathione, and play a critical role in cellular detoxification (2). With a icant reduction in cell survival (13). The glutathionylation of intracel- cysteine residue present in the active site instead of a tyrosine lular protein serves as an essential posttranslational modification mod- commonly found in other GSTs, GSTO1 carries distinct enzymatic ulating signal transduction (14, 15) and exerts diverse impact on cellular and metabolic functions. It plays important roles in biotransformation processes. The glutathionylation/deglutathionylation function positions of xenobiotics, glutathionylation, deglutathionylation, and redox GSTO1 as a key regulator of critical proteins in cell growth path- detoxification (3). GSTO1 overexpression and polymorphism corre- ways (16, 17). Moreover, GSTO1 is crucial in modulating the Toll-like late with several pathologic diseases including neurologic disorders, receptor 4 (TLR4)-mediated proinflammatory pathway (18), promoting cancers, and inflammatory diseases (3). NLRP3 inflammasome activation (19) and attenuating the release of GSTO1 is upregulated in several human cancers including esoph- proinflammatory cytokines including IL1b, IL6, and TNF (20), which ageal squamous cell carcinoma (4, 5), colorectal (5, 6), and urinary are important in the tumor immune environment. GSTO1 may signif- bladder cancer (7). However, how GSTO1 is mechanistically linked with icantly contribute to various pathologies; however, the roles of GSTO1 disease progression is largely unknown. GSTO1 overexpression is in cancer progression are largely unexplored. To fully characterize the roles of GSTO1 in cancer progression, we employed CRISPR/Cas9 to knockout GSTO1 in multiple cancer cell 1Department of Medicinal Chemistry, College of Pharmacy, University of Michi- lines and evaluated its impact using a variety of phenotypic and 2 gan, Ann Arbor, Michigan. Rogel Cancer Center, University of Michigan, Ann genomic profiling. Our results demonstrate that depletion of GSTO1 3 Arbor, Michigan. Department of Biostatistics and Department of Computational suppressed tumor growth in vivo and inhibited three-dimensional Medicine and Bioinformatics, Ann Arbor, Michigan. 4Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan. 5Department of Envi- (3D) spheroid growth in vitro. Using multiomics genome-wide pro- ronmental Health Sciences, University of Michigan, Ann Arbor, Michigan. filing [bromouridine nascent RNA sequencing (Bru-seq), RNA sequencing (RNA-seq), and MS proteomics], we have characterized Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). the transcriptional and translational response to GSTO1 deletion. Loss of GSTO1 caused transcriptional suppression of genes involved in cell- Corresponding Author: Nouri Neamati, University of Michigan-Ann Arbor, 1600 Huron Parkway, Bldg 520, Room 1363, Ann Arbor, MI 48109. Phone: 734-647- cycle checkpoints, as well as target genes for Myc and E2F transcription 2732; Fax: 323-442-1390; E-mail: [email protected] factors. Furthermore, genes and proteins involved in cell adhesion, IFNa, and IFNg response were enriched in GSTO1 KO cells. On the Cancer Res 2020;80:3692–705 basis of transcriptome signature of GSTO1 KO cells, we tested select doi: 10.1158/0008-5472.CAN-20-0530 FDA-approved drugs in GSTO1 KO cells and expanded the utility of Ó2020 American Association for Cancer Research. GSTO1 inhibitors in combination with standard-of-care drugs. AACRJournals.org | 3692 Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 2020 American Association for Cancer Research. Published OnlineFirst June 22, 2020; DOI: 10.1158/0008-5472.CAN-20-0530 Deletion of GSTO1 Activates IFN-I Genes and Downregulates F3 Cumulatively, our study demonstrates the significance of GSTO1 in Animal studies cancer progression, reveals extensive regulation of gene expression by Female NOD/SCID mice, 6- to 10-week-old, were used for implan- GSTO1, and further validates GSTO1 as a therapeutic target in cancer. tation of HCT116 survival experiments. Female ICRSC mice, 6- to 10- week-old, were used for implantation of HCT116 and U-87 MG tumor monitoring experiments. A total of 1  106 HCT116 or 2  106 U-87 Materials and Methods MG tumor cells were implanted subcutaneously into right flank Cell lines regions of mice. Tumor growth was monitored twice a week by digital HCT116 (ATCC, CCL-247) and GSTO1 KO cells were cultured in caliper and tumor volumes were calculated by the (length  width2)/2 RPMI1640 supplemented with 10% FBS. U-87 MG (generously pro- equation. Mice were sacrificed once tumors reached 1,500 mm3. The vided by Dr. Alan L. Epstein, University of Southern California, Los University of Michigan Institutional Animal Care and Use Committee Angeles, CA), A172 (ATCC, CRL-1620), and their related GSTO1 KO approved all animal experiments. cells were cultured in DMEM supplemented with 10% FBS. Cells were fi kept at 37 C in a humidi ed atmosphere of 5% CO2. All cell lines were Pan-disease gene expression analysis maintained in culture under 30 passages and tested regularly for Patient data described in this work were, in part, based upon data Mycoplasma contamination using PlasmoTest. generated by the The Cancer Genome Atlas (TCGA) Research Network: http://cancergenome.nih.gov/. Patient sample RNA-seq RSEM normal- Reagents ized gene expression values and related survival metadata were sourced CB-839, mitomycin C, cryptotanshinone, altretamine, GSK583, from the TCGA GDAC Firehose (21). When multiple samples were liproxstatin-1, spautin-1, PD-1/PD-L1 inhibitor 2, RVX-208, seli- available for a given patient, barcodes were sorted alphabetically and the nexor, ferrostatin-1, diacerein, LY2603618, and patupilone were pur- first was selected for analysis. A total of 9,718 samples were evaluated chased from Selleckchem. Cisplatin, carboplatin, and oxaliplatin were across 34 total disease groups. purchased from Sigma-Aldrich. Olaprib, niraparib, and veliparib were TCGA gene expression data downloaded from GDAC Firehose is purchased from Cayman Chemical. As2O3 was purchased from Bio- upper-quartile normalized for comparison within disease groups. To Tang. C1-27 is a GSTO1 inhibitor previously identified and synthe- survey GSTO1 expression across all 34 TCGA disease groups, we sized by our laboratory (5). normalized log2 RSEM expression values by calculating z-scores for each patient using the following steps for each patient: (i) calculate the CRISPR/Cas9-mediated genome editing patient mean and patient SD for all protein-coding gene expression GSTO1 KO cancer cell lines were generated using the Edit-R values; and (ii) Calculate GSTO1 z-score by subtracting the patient CRISPR-Cas9 system from Dharmacon (GE Healthcare). Edit-R mean and dividing by the patient SD. The resulting GSTO1 z-scores Lentiviral hEF1a-Blast-Cas9 lentiviral particles (generously provided are shown in Fig. 1A. by Phillip L. Palmbos, University of Michigan,
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