A CARM1 inhibitor potently suppresses breast cancer both in vitro and in vivo
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1017813 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26071054_1.fastq.gz | Fastqsanger.gz | |||
| SRR26071054_2.fastq.gz | Fastqsanger.gz | |||
| SRR26071055_1.fastq.gz | Fastqsanger.gz | |||
| SRR26071055_2.fastq.gz | Fastqsanger.gz | |||
| SRR26071056_1.fastq.gz | Fastqsanger.gz |
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Project description:CARM1, a member of the protein arginine methyltransferase (PRMT) family, regulates a variety of cellular processes. CARM1 overexpression and/or aberrant activation are tightly linked to cancer development, and it is considered as a promising therapeutic target for cancer diagnosis and therapy. However, the number of specific and potent CARM1 inhibitors is limited to date. We herein discovered a CARM1 inhibitor, iCARM1, showed better specificity and stronger activity towards CARM1 both in vitro and in vivo compared to the known CARM1 inhibitors EZM2302 and TP-064. Similar as CARM1 knockdown, iCARM1 suppressed the expression of oncogenic estrogen/ER-target genes, whereas activated type I interferon (IFN) and IFN-induced genes (ISGs) in breast cancer cells. Consequently, iCARM1 potently suppressed tumor growth in multiple mouse breast tumor models. Based on the gene programs iCARM1-regulated, combination therapy with iCARM1 and endocrine therapy drugs or etoposide exhibited synergetic effects in suppressing breast tumor growth. Taken together, we demonstrated that targeting CARM1 by iCARM1 is effective in suppressing CARM1-regulated gene program and breast cancer development, providing a therapeutic avenue for treating breast cancers in the clinic.
2024-06-12 | GSE243316 | GEO
Project description:A specific JMJD6 inhibitor potently suppresses multiple types of cancers both in vitro and in vivo
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Project description:Jumonji C-domain containing protein 6 (JMJD6), an iron (Fe2+) and a-ketoglutarate (a-KG)-dependent oxygenase, is expressed at high levels, correlated with poor prognosis, and considered as a therapeutic target in multiple cancer types. However, specific JMJD6 inhibitors that are potent in suppressing tumorigenesis have not been reported so far. We herein report that iJMJD6, a specific small-molecule inhibitor of JMJD6 with favorable physiochemical properties, inhibits the enzymatic activity of JMJD6 protein both in vitro and in cultured cells. iJMJD6 is effective in suppressing cell proliferation, migration, and invasion in multiple types of cancer cells in a JMJD6-dependent manner, while it exhibits minimal toxicity in normal cells. Mechanistically, iJMJD6 represses the expression of oncogenes including Myc and CCND1, in accordance with JMJD6 function in promoting the transcription of these genes. iJMJD6 exhibits suitable pharmacokinetic properties and suppresses tumor growth in multiple cancer cell line-and patient-derived xenograft models with safety. Furthermore, combination therapy with iJMJD6 and BET protein inhibitor (BETi) JQ1 or estrogen receptor antagonist fulvestrant exhibits synergistic effects in suppressing tumor growth. Taken together, we demonstrate that inhibition of JMJD6 enzymatic activity by using iJMJD6 is effective in suppressing oncogene expression and cancer development, providing a therapeutic avenue for treating cancers that are dependent on JMJD6 in clinic.
2022-08-31 | GSE201988 | GEO
Project description:Jumonji C-domain-containing protein 6 (JMJD6), an iron (Fe2+) and α-ketoglutarate (α-KG)-dependent oxygenase, is expressed at high levels, correlated with poor prognosis, and considered as a therapeutic target in multiple cancer types. However, specific JMJD6 inhibitors that are potent in suppressing tumorigenesis have not been reported so far. We herein report that iJMJD6, a specific small-molecule inhibitor of JMJD6 with favorable physiochemical properties, inhibits the enzymatic activity of JMJD6 protein both in vitro and in cultured cells. iJMJD6 is effective in suppressing cell proliferation, migration, and invasion in multiple types of cancer cells in a JMJD6-dependent manner, while it exhibits minimal toxicity in normal cells. Mechanistically, iJMJD6 represses the expression of oncogenes, including Myc and CCND1, in accordance with JMJD6 function in promoting the transcription of these genes. iJMJD6 exhibits suitable pharmacokinetic properties and suppresses tumor growth in multiple cancer cell line- and patient-derived xenograft models safely. Furthermore, combination therapy with iJMJD6 and BET protein inhibitor (BETi) JQ1 or estrogen receptor antagonist fulvestrant exhibits synergistic effects in suppressing tumor growth. Taken together, we demonstrate that inhibition of JMJD6 enzymatic activity by using iJMJD6 is effective in suppressing oncogene expression and cancer development, providing a therapeutic avenue for treating cancers that are dependent on JMJD6 in the clinic.
| S-EPMC9407455 | biostudies-literature
Project description:The goal of the project was global identification of CARM1 substrates. Arginine methylation landscapes were profiled and compared in wild type and CARM1 knockout cells to determine in vivo substrates of CARM1.
2017-07-03 | PXD005871 | Pride
Project description:The goal of this study is to identify ERalpha-target genes affected by overexpression of the histone arginine methyltransferase CARM1 in breast cancer cells. The roles of CARM1 in ERalpha+ breast cancer was not well characterized. Therefore, we created a Dox inducible CARM1 overexpressing MCF7 cell line where CARM1 is overexpressed by 2 fold to determine the created a Dox-inducible CARM1 overexpressing MCF7 cells for evaluation of the global effects of CARM1 on Eralpha-target gene expression. MCF7-tet-on-CARM1 clone 13 were treated under 4 conditions: DMSO; Dox; E2 (10nM); Dox+E2. In Dox+E2 condition, cells were pre-treated with Dox for 5 days before treating with E2 for 4 hours. 3 biological replicates were included and total of 12 samples were analyzed.
2011-06-01 | E-GEOD-26454 | biostudies-arrayexpress
Project description:The goal of this study is to identify ERalpha-target genes affected by knocking down of the histone arginine methyltransferase CARM1 in MCF7 breast cancer cells. The roles of CARM1 in ERalpha+ breast cancer was not well characterized. Therefore, we created a Dox inducible CARM1 knockingdown MCF7 cell line where CARM1 is decreased to 20% of endogeneous level to determine the created a Dox-inducible CARM1shRNA overexpressing MCF7 cells for evaluation of the global effects of CARM1 on ERalpha-target gene expression. MCF7-tet-on-CARM1shRNA clone 1 were treated under 4 conditions: DMSO; Dox; E2 (10nM); Dox+E2. In Dox+E2 condition, cells were pre-treated with Dox for 5 days before treating with E2 for 4 hours. 3 biological replicates were included and total of 12 samples were analyzed.
2011-06-01 | E-GEOD-26259 | biostudies-arrayexpress
Project description:We identified NFIB as a CARM1 substrate and showed that this transcription factor utilizes CARM1 as a coactivator. Importantly, NFIB harbors both oncogenic and metastatic activities, and is often overexpressed in small cell lung cancer (SCLC). Using a SCLC mouse model, we show that both CARM1 and the CARM1 methylation site on NFIB are critical for the rapid onset of SCLC. By performing the high-throughput sequecing analysis, we found that CARM1-null and NFIB-R388K mutant mouse SCLC tumors share the ability to regulate chromatin accessbility and have similar gene expression pattern.
2022-02-07 | GSE195843 | GEO
Project description:Transcript data from tibialis anterior muscle from male muscle-specific Coactivator-Associated Arginine Methyltransferase 1 (Carm1 ) knockout mice (Carm1 skm-/- ) and wild-type mice (Carm1 skm+/+) generated by using the Cre-loxP system (on a C57BL6J/129 background) with HSA-Cre mice (from Jackson laboratories). We used RNA-Seq to detail the effects of muscle-specific loss of Carm1 on the global program of gene expression in tibialis anterior muscle.
2022-08-24 | GSE189351 | GEO
Project description:We have found that Coactivator-associated Arginine Methyltransferase 1 (Carm1) mutant mice have highly penetrant heart defects. These are similar to those found in Pax3 mutant mice and PAX3 is a target of CARM1-mediated methylation. We analyzed gene expression at mid-gestation in both mutant lines.
2022-01-16 | GSE193588 | GEO