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Identify genes regulated by RUNX2, NCOR1, and HDAC3 in osteosarcoma cells

ABSTRACT: The dearth of molecular and cellular knowledge regarding the etiology of osteosarcoma (OS) impedes the advancement of innovative therapeutic interventions, such as immune therapy, for this debilitating childhood malignancy. Here, we report that Runt-related transcription factor 2 (RUNX2), along with nuclear receptor corepressor (NCOR1), inhibits OS cell senescence by downregulating the cGAS-STING-Type I Interferon (IFN-I) axis. We demonstrate that the NCOR1 gene is amplified in human OS tumors and is essential for tumor growth in xenograft mouse models. RUNX2 and NCOR1 function as regulatory “rheostats” by directly suppressing the expression of key transducer genes within the cGAS-STING-IFN-I pathway, including cGAS, STING, STAT1, STAT2, IRF7, and IRF9. During OS senescence induced by depletion of RUNX2 or NCOR1, endogenous retroviruses are aberrantly upregulated and reverse-transcribed, activating cGAS and initiating an elevated inflammatory cascade that includes programmed death-ligand 1 (PD-L1) upregulation. Inhibition of histone deacetylase 3 (HDAC3), a component of the NCOR1 complex, mirrors the effects observed with RUNX2 or NCOR1 depletion. Moreover, combining an HDAC3 inhibitor (HDAC3i) with an anti-PD-1 antibody results in sustained OS regression and increased CD8+ T cell activation in a mouse model. In conclusion, our findings identify RUNX2-NCOR1 as an epigenetic checkpoint modulating the innate immunity of OS cells, providing a rationale for the combined use of HDAC3i-targeted therapy and immune checkpoint blockade in OS treatment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE280227 | GEO | 2026/08/21

REPOSITORIES: GEO

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Effect of HDAC3 knockdown on H3K9ac in osteosarcoma cells

Project description:The dearth of molecular and cellular knowledge regarding the etiology of osteosarcoma (OS) impedes the advancement of innovative therapeutic interventions, such as immune therapy, for this debilitating childhood malignancy. Here, we report that Runt-related transcription factor 2 (RUNX2), along with nuclear receptor corepressor (NCOR1), inhibits OS cell senescence by downregulating the cGAS-STING-Type I Interferon (IFN-I) axis. We demonstrate that the NCOR1 gene is amplified in human OS tumors and is essential for tumor growth in xenograft mouse models. RUNX2 and NCOR1 function as regulatory “rheostats” by directly suppressing the expression of key transducer genes within the cGAS-STING-IFN-I pathway, including cGAS, STING, STAT1, STAT2, IRF7, and IRF9. During OS senescence induced by depletion of RUNX2 or NCOR1, endogenous retroviruses are aberrantly upregulated and reverse-transcribed, activating cGAS and initiating an elevated inflammatory cascade that includes programmed death-ligand 1 (PD-L1) upregulation. Inhibition of histone deacetylase 3 (HDAC3), a component of the NCOR1 complex, mirrors the effects observed with RUNX2 or NCOR1 depletion. Moreover, combining an HDAC3 inhibitor (HDAC3i) with an anti-PD-1 antibody results in sustained OS regression and increased CD8+ T cell activation in a mouse model. In conclusion, our findings identify RUNX2-NCOR1 as an epigenetic checkpoint modulating the innate immunity of OS cells, providing a rationale for the combined use of HDAC3i-targeted therapy and immune checkpoint blockade in OS treatment.

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Identify genes regulated by RUNX2, NCOR1, and HDAC3 in osteosarcoma cells

Project description:Identify genes regulated by RUNX2, NCOR1, and HDAC3 in osteosarcoma cells

| PRJNA1177401 | ENA

Syngergistic Effect of JQ1 and Rapamycin for Treatment of Human Osteosarcoma

Project description:Bromodomain and extra terminal domain (BET) proteins are important epigenetic regulators facilitating the transcription of genes in chromatin areas linked to acetylated histones. JQ1, a BET protein inhibitor, has antiproliferative activity against many cancers, mainly through inhibition of c-MYC and upregulation of p21. In this research, we investigated the use of JQ1 for human osteosarcoma (OS) treatment. JQ1 significantly inhibited the proliferation and survival of OS cells inducing G1 cell cycle arrest, premature senescence, but little effect on apoptosis. Interestingly, c-MYC protein levels in JQ1-treated cells remained unchanged, whereas the upregulation of p21 protein was still observable. Although effective in vitro, JQ1 alone failed to reduce the size of the MNNG/HOS xenografts in immunocompromised mice. To overcome the resistance of OS cells to JQ1 treatment, we combined JQ1 with rapamycin, an mTOR inhibitor. JQ1 and rapamycin synergistically inhibited the growth and survival of OS cells in vitro and in vivo. We also identified that RUNX2 is a direct target of BRD4 inhibition by JQ1 in OS cells. Chromatin immunoprecipitation (ChIP) showed that enrichment of BRD4 protein around RUNX2 transcription start sites diminished with JQ1 treatment in MNNG/HOS cells. Overexpression of RUNX2 protected JQ1-sensitive OS cells from the effect of JQ1, and siRNA-mediated inhibition of RUNX2 sensitized the same cells to JQ1. In conclusion, our findings suggest that JQ1, in combination with rapamycin, is an effective chemotherapeutic option for OS treatment. We also show that inhibition of RUNX2 expression by JQ1 partly explains antiproliferative activity of JQ1 in OS cells. MNNG/HOS cells treated with 7.5mM JQ1, 12.5nM Rapamycin or both were used for RNA extraction and hybridization on Affymetrix microarrays. We compared these microarray samples with the corresponding control (treated with DMSO).

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