scholarly journals Autochthonous tumors driven by Rb1 loss have an ongoing requirement for the RBP2 histone demethylase

2018 ◽  
Vol 115 (16) ◽  
pp. E3741-E3748 ◽  
Author(s):  
Samuel K. McBrayer ◽  
Benjamin A. Olenchock ◽  
Gabriel J. DiNatale ◽  
Diana D. Shi ◽  
Januka Khanal ◽  
...  
Keyword(s):  
Therapeutic Target ◽  
Histone Demethylase ◽  
Retinoblastoma Gene ◽  
Loss Of Function ◽  
Genetic Ablation ◽  
Tumor Bearing ◽  
Human Cancers ◽  
Promising Strategy ◽  
Downstream Effectors ◽  
Slow Tumor Growth

Inactivation of the retinoblastoma gene (RB1) product, pRB, is common in many human cancers. Targeting downstream effectors of pRB that are central to tumorigenesis is a promising strategy to block the growth of tumors harboring loss-of-function RB1 mutations. One such effector is retinoblastoma-binding protein 2 (RBP2, also called JARID1A or KDM5A), which encodes an H3K4 demethylase. Binding of pRB to RBP2 has been linked to the ability of pRB to promote senescence and differentiation. Importantly, genetic ablation of RBP2 is sufficient to phenocopy pRB’s ability to induce these cellular changes in cell culture experiments. Moreover, germline Rbp2 deletion significantly impedes tumorigenesis in Rb1+/− mice. The value of RBP2 as a therapeutic target in cancer, however, hinges on whether loss of RBP2 could block the growth of established tumors as opposed to simply delaying their onset. Here we show that conditional, systemic ablation of RBP2 in tumor-bearing Rb1+/− mice is sufficient to slow tumor growth and significantly extend survival without causing obvious toxicity to the host. These findings show that established Rb1-null tumors require RBP2 for growth and further credential RBP2 as a therapeutic target in human cancers driven by RB1 inactivation.

CDKN2A loss-of-function genetic alterations in uterine sarcoma: prognostic implications and potential therapeutic target

2021 ◽  
Vol 162 ◽  
pp. S48
Author(s):  
Kathryn Miller ◽  
Herman Chui ◽  
Sarah Chiang ◽  
Lora Ellenson ◽  
Britta Weigelt ◽  
...  
Keyword(s):  
Therapeutic Target ◽  
Genetic Alterations ◽  
Uterine Sarcoma ◽  
Loss Of Function ◽  
Potential Therapeutic Target ◽  
Prognostic Implications

scholarly journals Loss of Kallmann syndrome-associated gene WDR11 disrupts primordial germ cell development by affecting canonical and non-canonical Hedgehog signalling

2020 ◽  
Author(s):  
Jiyoung Lee ◽  
Yeonjoo Kim ◽  
Paris Ataliotis ◽  
Hyung-Goo Kim ◽  
Dae-Won Kim ◽  
...  
Keyword(s):  
Germ Cell ◽  
Germ Cells ◽  
Primary Cilia ◽  
Primordial Germ Cell ◽  
Kallmann Syndrome ◽  
Loss Of Function ◽  
Downstream Effectors ◽  
Cell Components ◽  
Underlying Mechanisms ◽  
And Migration

ABSTRACTMutations of WDR11 are associated with Kallmann syndrome (KS) and congenital hypogonadotrophic hypogonadism (CHH), typically caused by defective functions of gonadotrophin-releasing hormone (GnRH) neurones in the brain. We previously reported that Wdr11 knockout mice show profound infertility with significantly fewer germ cells present in the gonads. To understand the underlying mechanisms mediated by WDR11 in these processes, we investigated the effects of Wdr11 deletion on primordial germ cell (PGC) development. Using live-tracking of PGCs and primary co-cultures of genital ridges (GR), we demonstrated that Wdr11-deficient embryos contained reduced numbers of PGCs which had delayed migration due to significantly decreased proliferation and motility. We found primary cilia-dependent canonical Hedgehog (Hh) signalling was required for proliferation of the somatic mesenchymal cells of GR, while primary cilia-independent non-canonical Hh signalling mediated by Ptch2/Gas1 and downstream effectors Src and Creb was required for PGC proliferation and migration, which was disrupted by the loss of function mutations of WDR11. Therefore, canonical and non-canonical Hh signalling are differentially involved in the development of somatic and germ cell components of the gonads, and WDR11 is required for both of these pathways operating in parallel in GR and PGCs, respectively, during normal PGC development. Our study provides a mechanistic link between the development of GnRH neurones and germ cells mediated by WDR11, which may underlie some cases of KS/CHH and ciliopathies.

scholarly journals Lipidomic profiling reveals soluble epoxide hydrolase as a therapeutic target of obesity-induced colonic inflammation

2018 ◽  
Vol 115 (20) ◽  
pp. 5283-5288 ◽  
Author(s):  
Weicang Wang ◽  
Jun Yang ◽  
Jianan Zhang ◽  
Yuxin Wang ◽  
Sung Hee Hwang ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Therapeutic Target ◽  
Epoxide Hydrolase ◽  
Soluble Epoxide Hydrolase ◽  
Colon Tissue ◽  
Colonic Inflammation ◽  
Obesity Epidemic ◽  
Genetic Ablation ◽  
Endogenous Lipid ◽  
Novel Therapeutic

Obesity is associated with enhanced colonic inflammation, which is a major risk factor for colorectal cancer. Considering the obesity epidemic in Western countries, it is important to identify novel therapeutic targets for obesity-induced colonic inflammation, to develop targeted strategies for prevention. Eicosanoids are endogenous lipid signaling molecules involved in regulating inflammation and immune responses. Using an LC-MS/MS–based lipidomics approach, we find that obesity-induced colonic inflammation is associated with increased expression of soluble epoxide hydrolase (sEH) and its eicosanoid metabolites, termed fatty acid diols, in colon tissue. Furthermore, we find that pharmacological inhibition or genetic ablation of sEH reduces colonic concentrations of fatty acid diols, attenuates obesity-induced colonic inflammation, and decreases obesity-induced activation of Wnt signaling in mice. Together, these results support that sEH could be a novel therapeutic target for obesity-induced colonic inflammation and associated diseases.

LINC01133 hampers the development of gastric cancer through increasing SST via binding to microRNA-576-5p

Epigenomics ◽  
2021 ◽  
Author(s):  
Leiyi Zhang ◽  
Ke Pan ◽  
Zhongkun Zuo ◽  
Fei Ye ◽  
Ding Cao ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Tumor Growth ◽  
Nude Mice ◽  
Therapeutic Targets ◽  
Loss Of Function ◽  
Gain Of Function ◽  
Tumor Bearing ◽  
New Therapeutic Targets ◽  
Low Expression ◽  
Development Of Gastric Cancer

Aim: Our study aimed at investigating how LINC01133 functions in gastric cancer (GC) progression. Materials & methods: Gain-of-function and loss-of-function approaches were applied to analyze the effects of LINC01133, microRNA-576-5p (miR-576-5p) and somatostatin (SST) on the biological behaviors of GC cells and in tumor-bearing nude mice. Results: GC tissues and cells showed low expression of LINC01133, and LINC01133 overexpression decreased malignant phenotypes of GC cells. Moreover, LINC01133 upregulated SST through binding to miR-576-5p. Overexpressing miR-576-5p or suppressing SST reversed the functions of LINC01133 in biological potentials of GC cells and tumor growth. Conclusion: LINC01133 overexpression may inhibit GC development by downregulation of miR-576-5p and upregulation of SST, which suggests new therapeutic targets for GC.

scholarly journals A CRISPR/Cas9 screen identifies the histone demethylase MINA53 as a novel HIV-1 latency-promoting gene (LPG)

2019 ◽  
Vol 47 (14) ◽  
pp. 7333-7347 ◽  
Author(s):  
Huachao Huang ◽  
Weili Kong ◽  
Maxime Jean ◽  
Guillaume Fiches ◽  
Dawei Zhou ◽  
...  
Keyword(s):  
Local Level ◽  
Histone Demethylase ◽  
Host Factors ◽  
Epigenetic Mark ◽  
Combination Antiretroviral Therapy ◽  
Downstream Effectors ◽  
Infected Cells ◽  
Latent Hiv ◽  
Hiv 1

AbstractAlthough combination antiretroviral therapy is potent to block active replication of HIV-1 in AIDS patients, HIV-1 persists as transcriptionally inactive proviruses in infected cells. These HIV-1 latent reservoirs remain a major obstacle for clearance of HIV-1. Investigation of host factors regulating HIV-1 latency is critical for developing novel antiretroviral reagents to eliminate HIV-1 latent reservoirs. From our recently accomplished CRISPR/Cas9 sgRNA screens, we identified that the histone demethylase, MINA53, is potentially a novel HIV-1 latency-promoting gene (LPG). We next validated MINA53’s function in maintenance of HIV-1 latency by depleting MINA53 using the alternative RNAi approach. We further identified that in vitro MINA53 preferentially demethylates the histone substrate, H3K36me3 and that in cells MINA53 depletion by RNAi also increases the local level of H3K36me3 at LTR. The effort to map the downstream effectors unraveled that H3K36me3 has the cross-talk with another epigenetic mark H4K16ac, mediated by KAT8 that recognizes the methylated H3K36 and acetylated H4K16. Removing the MINA53-mediated latency mechanisms could benefit the reversal of post-integrated latent HIV-1 proviruses for purging of reservoir cells. We further demonstrated that a pan jumonji histone demethylase inhibitor, JIB-04, inhibits MINA53-mediated demethylation of H3K36me3, and JIB-04 synergizes with other latency-reversing agents (LRAs) to reactivate latent HIV-1.

scholarly journals Circular RNA: a novel biomarker and therapeutic target for human cancers

2019 ◽  
Vol 16 (2) ◽  
pp. 292-301 ◽  
Author(s):  
Bo Lei ◽  
Zhiqiang Tian ◽  
Weiping Fan ◽  
Bing Ni
Keyword(s):  
Therapeutic Target ◽  
Circular Rna ◽  
Human Cancers

scholarly journals Tolerance of DNA Replication Stress Is Promoted by Fumarate Through Modulation of Histone Demethylation and Enhancement of Replicative Intermediate Processing in Saccharomyces cerevisiae

Genetics ◽  
2019 ◽  
Vol 212 (3) ◽  
pp. 631-654 ◽  
Author(s):  
Faeze Saatchi ◽  
Ann L. Kirchmaier
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Dna Replication ◽  
Mammalian Cells ◽  
Cell Cancer ◽  
Replication Stress ◽  
Histone Demethylase ◽  
Loss Of Function ◽  
Cycle Enzyme ◽  
Link Type ◽  
Dna Replication Stress

Fumarase is a well-characterized TCA cycle enzyme that catalyzes the reversible conversion of fumarate to malate. In mammals, fumarase acts as a tumor suppressor, and loss-of-function mutations in the FH gene in hereditary leiomyomatosis and renal cell cancer result in the accumulation of intracellular fumarate—an inhibitor of α-ketoglutarate-dependent dioxygenases. Fumarase promotes DNA repair by nonhomologous end joining in mammalian cells through interaction with the histone variant H2A.Z, and inhibition of KDM2B, a H3 K36-specific histone demethylase. Here, we report that Saccharomyces cerevisiae fumarase, Fum1p, acts as a response factor during DNA replication stress, and fumarate enhances survival of yeast lacking Htz1p (H2A.Z in mammals). We observed that exposure to DNA replication stress led to upregulation as well as nuclear enrichment of Fum1p, and raising levels of fumarate in cells via deletion of FUM1 or addition of exogenous fumarate suppressed the sensitivity to DNA replication stress of htz1Δ mutants. This suppression was independent of modulating nucleotide pool levels. Rather, our results are consistent with fumarate conferring resistance to DNA replication stress in htz1Δ mutants by inhibiting the H3 K4-specific histone demethylase Jhd2p, and increasing H3 K4 methylation. Although the timing of checkpoint activation and deactivation remained largely unaffected by fumarate, sensors and mediators of the DNA replication checkpoint were required for fumarate-dependent resistance to replication stress in the htz1Δ mutants. Together, our findings imply metabolic enzymes and metabolites aid in processing replicative intermediates by affecting chromatin modification states, thereby promoting genome integrity.

P152 EVALUATING THE EFFICACY OF GLUTAMATE CARBOXYPEPTIDASE II (GCPII) INHIBITORS IN “WILD-TYPE” MICE: LESSONS LEARNED FROM THE DEDICATOR OF CYTOKINESIS 2 MUTANT MOUSE

2020 ◽  
Vol 26 (Supplement_1) ◽  
pp. S6-S6
Author(s):  
Diane Peters ◽  
Lauren Norris ◽  
Barbara Slusher
Keyword(s):  
Therapeutic Target ◽  
Activity Index ◽  
Disease Activity Index ◽  
Lessons Learned ◽  
Target Protein ◽  
Loss Of Function ◽  
Wild Type ◽  
Glutamate Carboxypeptidase Ii ◽  
Dss Colitis ◽  
Glutamate Carboxypeptidase

Abstract Background Glutamate carboxypeptidase II (GCPII) is highly upregulated in human IBD and is a therapeutic target under active investigation by our laboratory. We recently published that a spontaneously occurring loss-of-function mutation in dedicator of cytokinesis 2 (Dock2Hsd) that was present in commercially-purchased “wild-type” C57Bl6/NHsd mice increased their sensitivity to DSS-colitis and caused them to closely resemble human IBD with respect to GCPII. The DSS-exposed Dock2Hsd mice had significantly elevated colon GCPII activities and were sensitive to treatment with the GCPII inhibitor, 2-PMPA. We hypothesized that if colitis of the same severity were to be induced in Dock2WT mice, that they would also exhibit heightened colon GCPII activity and would be equally sensitive to 2-PMPA treatment. Methods DSS-colitis was induced in weight-, age- and gender-matched C57Bl/6NHsd mice (Dock2Hsd and Dock2WT). Increasing concentrations of DSS were utilized (2.5%-4.0%) and disease activity index was monitored daily. Mice received once daily treatment with vehicle or GCPII inhibitor 2-PMPA (IP). Results With increased DSS concentrations (4%), a severe colitis could be established in the Dock2WT mice which closely resembled the disease seen in Dock2Hsd mice induced with 2.5% DSS. Interestingly, despite similarity in DAI scores and disease progression, the GCPII activity in colons of Dock2WT mice (4% DSS) remained significantly lower than that of Dock2Hsd mice (2.5% DSS) (p<0.001, t-test). Further, while 2-PMPA was effective in both groups, higher systemic doses were required in the IBD-resistant Dock2WT mice. Conclusions Following identification that the spontaneously occurring mutation Dock2Hsd influences murine DSS-colitis sensitivity and alters the activity of our therapeutic target protein, GCPII, in the colon, we sought to re-establish our DSS model using Dock2WT mice. While we were successfully able to recapitulate disease severity in the Dock2WT mice by increasing the DSS concentration from 2.5% to 4%, the underlying disease biology was not conserved. Despite having comparable DAI scores at study termination, Dock2WT mice had decreased GCPII activity in their colons relative to Dock2Hsd mice and were less sensitive to inhibition with the GCPII inhibitor, 2-PMPA. These data caution that target protein expression must be verified even with subtle changes to experimental method when utilizing the DSS-colitis model.

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