The potential of KDM3A as a therapeutic target in Ewing Sarcoma and other cancers

Jedlicka, Paul

doi:10.1080/14728222.2017.1391791

Cited by 7 publications

(7 citation statements)

References 17 publications

(28 reference statements)

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“…KDM3A has also been shown to be upregulated in expression, and to be involved in diseasepromoting properties, in numerous other cancers (as recently reviewed in [9]). This, along with its restricted expression and relative paucity of essential functions, has pointed to KDM3A as a potentially attractive therapeutic target [10]. Our previous studies noted robust expression of KDM3A in RMS cell lines [7], prompting further investigation into its potential role(s), as a diseasepromoting factor and candidate therapeutic target, in RMS.…”

Section: Rhabdomyosarcomamentioning

confidence: 88%

KDM3A/Ets1/MCAM axis promotes growth and metastatic properties in Rhabdomyosarcoma

et al. 2020

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Rhabdomyosarcoma (RMS) is the most common soft tissue malignancy of childhood. RMS exists as two major disease subtypes, with oncofusion-positive RMS (FP-RMS) typically carrying a worse prognosis than oncofusion-negative RMS (FN-RMS), in part due to higher propensity for metastasis. Epigenetic mechanisms have recently emerged as critical players in the pathogenesis of pediatric cancers, as well as potential new therapeutic vulnerabilities. Herein, we show that the epigenetic regulator KDM3A, a member of the Jumonji-domain histone demethylase (JHDM) family, is overexpressed, potently promotes colony formation and transendothelial invasion, and activates the expression of genes involved in cell growth, migration and metastasis, in both FN-RMS and FP-RMS. In mechanistic studies, we demonstrate that both RMS subtypes utilize a KDM3A/Ets1/MCAM disease-promoting axis recently discovered in Ewing Sarcoma, another aggressive pediatric cancer of distinct cellular and molecular origin. We further show that KDM3A depletion in FP-RMS cells inhibits both tumor growth and metastasis in vivo, and that RMS cells are highly sensitive to colony growth inhibition by the pan-JHDM inhibitor JIB-04. Together, our studies reveal an important role for the KDM3A/Ets1/MCAM axis in pediatric sarcomas of distinct cellular and molecular ontogeny, and identify new targetable vulnerabilities in RMS.

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Section: Rhabdomyosarcomamentioning

confidence: 88%

KDM3A/Ets1/MCAM axis promotes growth and metastatic properties in Rhabdomyosarcoma

et al. 2020

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“…Their following study in 2017 further demonstrated that KDM3A positively regulated metastasis-related genes in Ewing Sarcoma [ 16 ]. Based on this research, KDM3A was then suggested as a candidate therapeutic target for Ewing Sarcoma treatment [ 34 ]. However, compared to the known effect of KDM3A in Ewing Sarcoma, less is known regarding its function in the more common type of bone tumor OS.…”

Section: Discussionmentioning

confidence: 99%

KDM3A-mediated SP1 activates PFKFB4 transcription to promote aerobic glycolysis in osteosarcoma and augment tumor development

Wang

2022

BMC Cancer

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Background Lysine-specific histone demethylase 3A (KDM3A) is a potent histone modifier that is frequently implicated in the progression of several malignancies. However, its role in aerobic glycolysis of osteosarcoma (OS) remains unclear. Methods KDM3A expression in OS tissues was determined by immunohistochemistry, and that in acquired OS cells was determined by RT-qPCR and western blot assays. KDM3A was silenced in OS cells to examine cellular behaviors and the aerobic glycolysis. Stably transfected cells were injected into nude mice for in vivo experiments. The downstream targets of KDM3A were predicted by bioinformatics systems and validated by ChIP-qPCR. Rescue experiments of SP1 and PFKFB4 were performed to examine their roles in the KDM3A-mediated events. Results KDM3A was highly expressed in OS tissues and cells. Knockdown of KDM3A weakened OS cell growth and metastasis in vivo and in vitro, and it suppressed the aerobic glycolysis in OS cells. KDM3A enhanced the transcription of SP1 by demethylating H3K9me2 on its promoter. Restoration of SP1 rescued growth and metastasis of OS cells and recovered the glycolytic flux in cells suppressed by knockdown of KDM3A. SP1 bound to the PFKFB4 promoter to activate its transcription and expression. PFKFB4 expression in OS cells was suppressed by KDM3A silencing but increased after SP1 restoration. Overexpression of PFKFB4 significantly promoted OS cell growth and metastasis as well as the glycolytic flux in cells. Conclusion This paper elucidates that upregulation of PFKFB4 mediated by the KDM3A-SP1 axis promotes aerobic glycolysis in OS and augments tumor development.

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“…In previous studies, our group demonstrated disease-promoting properties for the Jumonji-domain histone demethylase (JHDM) KDM3A in Ewing sarcoma [ 19 – 21 ], as well as pre-clinical efficacy of a pan-JHDM inhibitor in this disease [ 22 ]. Seeking to further understand the biology of JHDMs in Ewing sarcoma, we noted the JHDMs KDM5A (JARID1A/RBBP2) and PHF2 (KDM7C/JHDM1E) to be consistently upregulated in expression in patient-derived Ewing sarcoma cell lines, relative to mesenchymal stem cells, the putative disease cell of origin ( Figure 1A ).…”

Section: Resultsmentioning

confidence: 99%

“…Recent studies have increasingly demonstrated a critical role for epigenetic mechanisms in Ewing sarcoma pathogenesis. This includes identification of important roles played by the NuRD repressor complex and LSD1 [14], BMI1 [15], EZH2 [8], members of the BET bromodomain family [16][17][18], the chromatin remodeling BAF complex [6], and KDM3A (our prior studies [19][20][21]). As broad regulators of gene expression, like EWS/ Fli1 itself, epigenetic modifiers have the potential to exert profound effects on disease phenotypes.…”

Section: Introductionmentioning

confidence: 99%

KDM5A and PHF2 positively control expression of pro-metastatic genes repressed by EWS/Fli1, and promote growth and metastatic properties in Ewing sarcoma

et al. 2020

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Ewing sarcoma is an aggressive malignant neoplasm with high propensity for metastasis and poor clinical outcomes. The EWS/Fli1 oncofusion is the disease driver in > 90% of cases, but presents a difficult therapeutic target. Moreover, EWS/Fli1 plays a complex role in disease progression, with inhibitory effects on critical steps of metastasis. Like many other pediatric cancers, Ewing sarcoma is a disease marked by epigenetic dysregulation. Epigenetic mechanisms present alternative targeting opportunities, but their contributions to Ewing sarcoma metastasis and disease progression remain poorly understood. Here, we show that the epigenetic regulators KDM5A and PHF2 promote growth and metastatic properties in Ewing sarcoma, and, strikingly, activate expression many pro-metastatic genes repressed by EWS/Fli1. These genes include L1CAM, which is associated with adverse outcomes in Ewing sarcoma, and promotes migratory and invasive properties. KDM5A and PHF2 retain their growth promoting effects in more metastatically potent EWS/Fli1 low cells, and PHF2 promotes both invasion and L1CAM expression in this cell population. Furthermore, KDM5A and PHF2 each contribute to the increased metastatic potency of EWS/Fli1 low cells in vivo . Together, these studies identify KDM5A and PHF2 as novel disease-promoting factors, and potential new targets, in Ewing sarcoma, including the more metastatically potent EWS/Fli1 low cell population.

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The potential of KDM3A as a therapeutic target in Ewing Sarcoma and other cancers

Cited by 7 publications

References 17 publications

KDM3A/Ets1/MCAM axis promotes growth and metastatic properties in Rhabdomyosarcoma

KDM3A/Ets1/MCAM axis promotes growth and metastatic properties in Rhabdomyosarcoma

KDM3A-mediated SP1 activates PFKFB4 transcription to promote aerobic glycolysis in osteosarcoma and augment tumor development

KDM5A and PHF2 positively control expression of pro-metastatic genes repressed by EWS/Fli1, and promote growth and metastatic properties in Ewing sarcoma

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