Many long noncoding RNAs (lncRNAs) are reported to be dysregulated in human cancers and play critical roles in tumor development and progression. Furthermore, it has been reported that many lncRNAs regulate gene expression by recruiting chromatin remodeling complexes to specific genomic loci or by controlling transcriptional or posttranscriptional processes. Here we show that an lncRNA termed UPAT [ubiquitin-like plant homeodomain (PHD) and really interesting new gene (RING) finger domaincontaining protein 1 (UHRF1) Protein Associated Transcript] is required for the survival and tumorigenicity of colorectal cancer cells. UPAT interacts with and stabilizes the epigenetic factor UHRF1 by interfering with its β-transducin repeat-containing protein (TrCP)-mediated ubiquitination. Furthermore, we demonstrate that UHRF1 up-regulates Stearoyl-CoA desaturase 1 and Sprouty 4, which are required for the survival of colon tumor cells. Our study provides evidence for an lncRNA that regulates protein ubiquitination and degradation and thereby plays a critical role in the survival and tumorigenicity of tumor cells. Our results suggest that UPAT and UHRF1 may be promising molecular targets for the therapy of colon cancer.A mong the RNA products transcribed from the mammalian genome are numerous long noncoding RNAs (lncRNAs)-that is, RNAs longer than 200 nucleotides with little or no protein-coding potential (1, 2). Many lncRNAs are expressed in a developmentally regulated and cell type-dependent manner (3, 4). Increasing evidence suggests that lncRNAs play critical roles in a diverse set of biological processes, including proliferation, differentiation, embryogenesis, neurogenesis, and stem cell pluripotency (5, 6).It has been reported that many lncRNAs regulate gene expression by recruiting chromatin remodeling complexes to specific genomic regions (2). It has also been shown that many lncRNAs regulate transcription by modulating the activity of transcriptional regulators (1, 6-8). lncRNAs also regulate various posttranscriptional processes, including splicing, transport, translation, and degradation of mRNA. Furthermore, recent studies have shown that a number of lncRNAs play critical roles in tumor development and progression.UHRF1 [ubiquitin-like plant homeodomain (PHD) and really interesting new gene (RING) finger domain-containing protein 1] is an epigenetic factor that consists of multiple domains (9). UHRF1 regulates transcription by regulating DNA methylation and histone modification. UHRF1 also possesses E3 ubiquitin ligase activity and ubiquitinates histones and DNA methyltransferase 1 (DNMT1), thereby regulating the chromatin structure and stability of DNMT1 (10, 11). UHRF1 plays key roles in multiple biological processes, including proliferation and development. Furthermore, UHRF1 is overexpressed in various tumors, including colon, breast, bladder, prostate, and lung cancers, and plays a critical role in the proliferation and survival of tumor cells (9).In the present study, we attempted to identify lncRNAs criti...
Wnt/β-catenin signaling plays a key role in the tumorigenicity of colon cancer. Furthermore, it has been reported that lncRNAs are dysregulated in several steps of cancer development. Here we show that β-catenin directly activates the transcription of the long noncoding RNA (lncRNA) ASBEL [antisense ncRNA in the ANA (Abundant in neuroepithelium area)/BTG3 (B-cell translocation gene 3) locus] and transcription factor 3 (TCF3), both of which are required for the survival and tumorigenicity of colorectal cancer cells. ASBEL interacts with and recruits TCF3 to the activating transcription factor 3 (ATF3) locus, where it represses the expression of ATF3. Furthermore, we demonstrate that ASBEL-TCF3-mediated down-regulation of ATF3 expression is required for the proliferation and tumorigenicity of colon tumor cells. ATF3, in turn, represses the expression of ASBEL. Our results reveal a pathway involving an lncRNA and two transcription factors that plays a key role in Wnt/β-catenin-mediated tumorigenesis. These results may provide insights into the variety of biological and pathological processes regulated by Wnt/β-catenin signaling.β-catenin | noncoding RNA | ASBEL | colorectal tumorigenesis | ATF3
Background Mixed lineage leukemia 1-rearranged (MLL1-r) acute leukemia patients respond poorly to currently available treatments and there is a need to develop more effective therapies directly disrupting the Menin‒MLL1 complex. Small-molecule–mediated inhibition of the protein‒protein interaction between Menin and MLL1 fusion proteins is a potential therapeutic strategy for patients with MLL1-r or mutated-nucleophosmin 1 (NPM1c) acute leukemia. In this study, we preclinically evaluated the new compound DS-1594a and its salts. Methods We evaluated the preclinical efficacy of DS-1594a as well as DS-1594a·HCl (the HCl salt of DS-1594a) and DS-1594a·succinate (the succinic acid salt of DS-1594a, DS-1594b) in vitro and in vivo using acute myeloid leukemia (AML)/acute lymphoblastic leukemia (ALL) models. Results Our results showed that MLL1-r or NPM1c human leukemic cell lines were selectively and highly sensitive to DS-1594a·HCl, with 50% growth inhibition values < 30 nM. Compared with cytrabine, the standard chemotherapy drug as AML therapy, both DS-1594a·HCl and DS-1594a·succinate mediated the eradication of potential leukemia-initiating cells by enhancing differentiation and reducing serial colony-forming potential in MLL1-r AML cells in vitro. The results were confirmed by flow cytometry, RNA sequencing, RT‒qPCR and chromatin immunoprecipitation sequencing analyses. DS-1594a·HCl and DS-1594a·succinate exhibited significant antitumor efficacy and survival benefit in MOLM-13 cell and patient-derived xenograft models of MLL1-r or NPM1c acute leukemia in vivo. Conclusion We have generated a novel, potent, orally available small-molecule inhibitor of the Menin-MLL1 interaction, DS-1594a. Our results suggest that DS-1594a has medicinal properties distinct from those of cytarabine and that DS-1594a has the potential to be a new anticancer therapy and support oral dosing regimen for clinical studies (NCT04752163).
We have developed a technology for efficiently enhancing the anticancer apoptosis-inducing activity of agonistic antibodies against the tumor necrosis factor receptor (TNFR) superfamily by the formation of immunoliposomes. To induce apoptosis in cancer cells, agonistic antibodies to the TNFR superfamily normally need cross-linking by internal immune effector cells via the Fc region after binding to receptors on the cell membrane. To develop apoptosis-inducing antibodies that do not require the support of cross-linking by immune cells, we prepared immunoliposomes conjugated with TRA-8, an agonistic antibody against death receptor 5 (DR5), with various densities of antibody on the liposome surface, and evaluated their activities. The TRA-8 immunoliposomes exhibited apoptosis-inducing activity against various DR5-positive human carcinoma cells at a significantly lower concentration without cross-linking than that of the original TRA-8 and its natural ligand (TRAIL). The activity of the immunoliposomes was correlated with the density of antibodies on the surface. As the antibody component, not only the full-length antibody but also the Fab' fragment could be used, and the TRA-8 Fab' immunoliposomes also showed exceedingly high activity compared with the parental antibody, namely, TRA-8. Moreover, cytotoxicity of the TRA-8 full-length or Fab' immunoliposome against normal cells, such as human primary hepatocytes, was lower than that for TRAIL. Enhanced activity was also observed for immunoliposomes conjugated with other apoptosis-inducing antibodies against other receptors of the TNFR superfamily, such as death receptor 4 (DR4) and Fas. Thus, immunoliposomes are promising as a new modality that could exhibit significant activity at a low dose, for cost-effective application of an antibody fragment and with stable efficacy independent of the intratumoral environment of patients as a TNF superfamily agonistic therapy.
DS-M1 is a novel, potent, orally bioavailable small molecule inhibitor of the binding of MLL1 fusion proteins and wild-type MLL1 to Menin in development for the treatment of patients with MLL1-rearranged (MLL1-r) or NPM1-mutated (NPM1-mu) acute leukemia. The interaction of MLL1 fusion proteins with menin plays an important role to enhance the proliferation and block the differentiation of hematopoietic cells, ultimately leading to acute leukemia. Furthermore, patients with MLL1-r acute leukemia respond poorly to currently available treatments, emphasizing the urgent need to develop more effective therapies directly disrupting the menin-MLL1 complex. Here we describe the characterization of DS-M1 and this study demonstrates the mechanism of action of DS-M1 as well as supports the oral dosing regimen planned for the initial clinical studies. DS-M1 selectively inhibited the cellular growth of MLL1-r or NPM1-mu human leukemic cell lines and primary cells from patients with GI50 of less than about 100 nM along with the cellular differentiation in vitro. RNA-seq and ChIP-seq analysis revealed that DS-M1 reduced the expression levels of MEIS1, PBX3 and HOXA9 genes in a concentration-dependent manner and dissociated the menin-MLL1 complex from the MEIS1 gene locus in MV-4-11, MOLM-13, and patient derived AML cells with MLL1-rearrangement. Interestingly, DS-M1 reduced the number of CD34+/CD38- leukemic stem cells (LSCs) in patient derived AML cells and induction of differentiation was also confirmed as measured by increased CD11b or CD14 expression. These results suggest that enhanced differentiation and loss of LSCs via the reduction of MEIS1, HOXA9, and PBX3 gene expression by DS-M1 is one of the main mechanisms of action for the antitumor activity of DS-M1. DS-M1 demonstrates significant survival benefit along with inhibition of MEIS1, HOXA9 and PBX3 expression in aggressive disseminated leukemia models intravenously inoculated with MV-4-11 and MOLM-13 cells as well as in patient-derived xenograft (PDX) models of MLL1-r or NPM1-mu acute leukemia. In disseminated MOLM-13 xenografts, treatment with 100 mg/kg qd of DS-M1 for 19 days produced durable response with event free survival >100 days after last dose (5 out of 6 mice, increase in life span (ILS) >515%). Furthermore, MLL1-r pediatric B-ALL-PDX mice treated with 50 mg/kg bid for 28 days and NPM1-mu AML-PDX mice treated with 100 mg/kg bid for 35 days were all survived (ILS >254% and >300%) without any detectable leukemic blast cells in bone marrow at 120 and 60 days after cessation of therapy, respectively. These data indicate that DS-M1 has a high potency as an antitumor drug with the potential to provide survival advantage in acute leukemia patients with MLL-r and NPM1-mu. Currently, a Phase 1/2 clinical study of DS-M1 is planned in AML and ALL patients with MLL-r or NPM1-mu. Citation Format: Masashi Numata, Machiko Shiroishi, Kenji Yoshikawa, Noriyasu Haginoya, Tsuyoshi Hirata, Yoshimi Takata, Reina Nagase, Kohei Takashima, Akiko Kurimoto, Fumie Tanzawa, Yumiko Tomoe, Tomoaki Hamada, Ryutaro Kanada, Jun Watanabe, Yoshiko Kagoshima, Eri Tokumaru, Kenji Murata, Takayuki Baba, Taeko Shinozaki, Kazuyuki Hashimoto, Motohiro Kato, Shinji Tsutsumi, Mayumi Kitagawa, Kosaku Fujiwara, Yuki Abe. Development and characterization of a novel orally bioavailable menin-MLL inhibitor for treatment of acute leukemia patients with MLL-rearrangement or NPM1 mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1132.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.