Browsing by Author "Jin, Jiamin"

Now showing 1 - 4 of 4
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    Inhibition of PRMT5 by market drugs as a novel cancer therapeutic avenue
    (Elsevier, 2023-01) Prabhu, Lakshmi; Martin, Matthew; Chen, Lan; Demir, Özlem; Jin, Jiamin; Huang, Xiumei; Motolani, Aishat; Sun, Mengyao; Jiang, Guanglong; Nakshatri, Harikrishna; Fishel, Melissa L.; Sun, Steven; Safa, Ahmad; Amaro, Rommie E.; Kelley, Mark R.; Liu, Yunlong; Zhang, Zhong-Yin; Lu, Tao; Radiation Oncology, School of Medicine
    Market drugs, such as Food and Drug Administration (FDA) or European Medicines Agency (EMA)-approved drugs for specific indications provide opportunities for repurposing for newer therapeutics. This potentially saves resources invested in clinical trials that verify drug safety and tolerance in humans prior to alternative indication approval. Protein arginine methyltransferase 5 (PRMT5) overexpression has been linked to promoting the tumor phenotype in several cancers, including pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC), and breast cancer (BC), making PRMT5 an important target for cancer therapy. Previously, we showed that PRMT5-mediated methylation of the nuclear factor (NF)-κB, partially contributes to its constitutive activation observed in cancers. In this study, we utilized an AlphaLISA-based high-throughput screening method adapted in our lab, and identified one FDA-approved drug, Candesartan cilexetil (Can, used in hypertension treatment) and one EMA-approved drug, Cloperastine hydrochloride (Clo, used in cough treatment) that had significant PRMT5-inhibitory activity, and their anti-tumor properties were validated using cancer phenotypic assays . Furthermore, PRMT5 selective inhibition of methyltransferase activity was confirmed by reduction of both NF-κB methylation and its subsequent activation upon drug treatment. Using prediction, we identified critical residues on PRMT5 targeted by these drugs that may interfere with its enzymatic activity. Finally, Clo and Can treatment have exhibited marked reduction in tumor growth . Overall, we provide basis for pursuing repurposing Clo and Can as anti-PRMT5 cancer therapies. Our study offers potential safe and fast repurposing of previously unknown PRMT5 inhibitors into clinical practice.
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    KDM2A Deficiency in the Liver Promotes Abnormal Liver Function and Potential Liver Damage
    (MDPI, 2023-09-27) Martin, Matthew; Motolani, Aishat; Kim, Hyeong-Geug; Collins, Amy M.; Alipourgivi, Faranak; Jin, Jiamin; Wei, Han; Wood, Barry A.; Ma, Yao-Ying; Dong, X. Charlie; Mirmira, Raghavendra G.; Lu, Tao; Pharmacology and Toxicology, School of Medicine
    Dysregulation of metabolic functions in the liver impacts the development of diabetes and metabolic disorders. Normal liver function can be compromised by increased inflammation via the activation of signaling such as nuclear factor (NF)-κB signaling. Notably, we have previously identified lysine demethylase 2A (KDM2A)—as a critical negative regulator of NF-κB. However, there are no studies demonstrating the effect of KDM2A on liver function. Here, we established a novel liver-specific Kdm2a knockout mouse model to evaluate KDM2A’s role in liver functions. An inducible hepatic deletion of Kdm2a, Alb-Cre-Kdm2afl/fl (Kdm2a KO), was generated by crossing the Kdm2a floxed mice (Kdm2afl/fl) we established with commercial albumin-Cre transgenic mice (B6.Cg-Tg(Alb-cre)21Mgn/J). We show that under a normal diet, Kdm2a KO mice exhibited increased serum alanine aminotransferase (ALT) activity, L-type triglycerides (TG) levels, and liver glycogen levels vs. WT (Kdm2afl/fl) animals. These changes were further enhanced in Kdm2a liver KO mice in high-fat diet (HFD) conditions. We also observed a significant increase in NF-κB target gene expression in Kdm2a liver KO mice under HFD conditions. Similarly, the KO mice exhibited increased immune cell infiltration. Collectively, these data suggest liver-specific KDM2A deficiency may enhance inflammation in the liver, potentially through NF-κB activation, and lead to liver dysfunction. Our study also suggests that the established Kdm2afl/fl mouse model may serve as a powerful tool for studying liver-related metabolic diseases.
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    PRMTs and miRNAs: functional cooperation in cancer and beyond
    (Taylor & Francis, 2019-06-24) Jin, Jiamin; Martin, Matthew; Hartley, Antja-Voy; Lu, Tao; Pharmacology and Toxicology, School of Medicine
    Epigenetic modulators play pivotal roles in directing gene expression for the maintenance of normal cellular functions. However, when these modulators are aberrantly regulated, this can result in a variety of disease states, including cancer. One class of epigenetic regulators, protein arginine methyltransferases (PRMTs), have been shown to play critical roles in disease through methylation of arginine residues (R) on histone or non-histone proteins. Quite different from PRMTs, microRNAs (miRNAs) belong to the family of modulators known as noncoding RNAs (ncRNA) that act to regulate gene expression via RNA-mediated gene silencing. Importantly, miRNAs are frequently dysregulated and contribute to the progression of cancer and other conditions, including neurological and cardiovascular diseases. Recently, numerous studies have shown that miRNAs and other epigenetic enzymes can co-regulate each other. This review highlights multiple nodes of interaction between miRNAs and PRMTs and also discusses how this interplay might open up promising opportunities for drug development for the treatment of cancer and other diseases.
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    Using VBIM Technique to Discover ARMC4/ODAD2 as a Novel Negative Regulator of NF-κB and a New Tumor Suppressor in Colorectal Cancer
    (MDPI, 2022-03-01) Martin, Matthew; Mundade, Rasika; Hartley, Antja-Voy; Jiang, Guanglong; Jin, Jiamin; Sun, Steven; Safa, Ahma; Sandusky, George; Liu, Yunlong; Lu, Tao; Pharmacology and Toxicology, School of Medicine
    Since nuclear factor (NF) κB plays pivotal roles in inflammation and cancer, understanding its regulation holds great promise for disease therapy. Using the powerful validation-based insertional mutagenesis (VBIM) technique established by us previously, we discovered armadillo repeat-containing protein 4 (ARMC4)/outer dynein arm docking complex subunit 2 (ODAD2), a rarely studied protein known to date, as a novel negative regulator of NF-κB in colorectal cancer (CRC). High expression of ARMC4 downregulated the expression of NF-κB-dependent genes, dramatically reduced NF-κB activity, cellular proliferation, anchorage-independent growth, and migratory ability in vitro, and significantly decreased xenograft tumor growth in vivo. Co-immunoprecipitation experiments demonstrated that ARMC4 forms a complex with NF-κB. Importantly, the lower ARMC4 expression in patient tumors than normal tissues indicates its potential tumor suppressor function in CRC. Collectively, we uncovered a completely new facet of ARMC4 function by identifying it as a novel NF-κB negative regulator, thus uncovering ARMC4 as a potential new therapeutic target in CRC.