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KDM4C inhibition blocks tumor growth in basal breast cancer by promoting cathepsin L-mediated histone H3 cleavage

ABSTRACT: Triple-negative breast cancer (TNBC) is a highly aggressive disease with inferior prognosis necessitating the discovery of novel actionable targets. Here, we show that KDM4C, a histone demethylase amplified in a subset of TNBC, is a driver of TNBC tumor growth. Integrative multi-omic analysis demonstrated that KDM4C inhibition triggers chromatin and transcriptomic remodeling without substantial changes of its canonical substrates H3K9me3 and H3K36me3. Rather KDM4C loss caused proteolytic cleavage of histone H3 mediated by cathepsin L (CTSL) recruited to the chromatin by GRHL2. Metabolomic profiling showed reduced glutathione levels following KDM4C inhibition partly due to a decrease in glutamate-cysteine ligase (GCLC) caused by CTSL-mediated histone H3 cleavage and led to increased reactive oxygen species. The expression of KDM4C and GCLC correlated in TNBC and combined targeting of KDM4C and the GSH axis improved response to cisplatin in TNBC. Our study reveals a novel, non-canonical role for KDM4C in TNBC that links metabolic and epigenetic profiles.

ORGANISM(S): Homo sapiens

PROVIDER: GSE199913 | GEO | 2025/03/23

REPOSITORIES: GEO

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KDM4C histone demethylase connects chromatin remodeling and metabolism in triple-negative breast cancer

Project description:Triple-negative breast cancer (TNBC) is a highly aggressive disease with inferior prognosis necessitating the discovery of novel actionable targets. Here, we show that KDM4C, a histone demethylase amplified in a subset of TNBC, is a driver of TNBC tumor growth. Integrative multi-omic analysis demonstrated that KDM4C inhibition triggers chromatin and transcriptomic remodeling without substantial changes of its canonical substrates H3K9me3 and H3K36me3. Rather KDM4C loss caused proteolytic cleavage of histone H3 mediated by cathepsin L (CTSL) recruited to the chromatin by GRHL2. Metabolomic profiling showed reduced glutathione levels following KDM4C inhibition partly due to a decrease in glutamate-cysteine ligase (GCLC) leading to increased reactive oxygen species and activation of CTSL. The expression of KDM4C and GCLC correlated in TNBC and combined targeting of KDM4C and GSH axis improved response to cisplatin in TNBC. Our study reveals a novel, non-canonical role for KDM4C in TNBC that links metabolic and epigenetic profiles.

2025-04-12 | PXD031768 | Pride

GRHL2 methylation links KDM4C activity to cathepsin L-mediated histone H3 cleavage

Project description:Basal breast cancer is a subtype with inferior prognosis necessitating novel therapeutic targets. Here, we describe a unique role for the KDM4C histone lysine demethylase in KDM4C-amplified basal breast cancers, where KDM4C inhibition triggers chromatin and transcriptomic remodeling without substantial changes of its canonical substrates H3K9me3 and H3K36me3. Rather KDM4C loss causes proteolytic cleavage of histone H3 mediated by cathepsin L (CTSL) resulting in decreased glutamate-cysteine ligase expression and increased reactive oxygen species (ROS). CTSL is recruited to the chromatin by the GRHL2 transcription factor that is methylated at lysine 453 following KDM4C inhibition triggering CTSL histone clipping activity. Deletion of CTSL or inhibition of ROS rescued KDM4-loss-mediated tumor suppression. Our study reveals a novel function for KDM4C that links cellular redox regulation to chromatin remodeling.

2025-01-24 | MSV000096930 | MassIVE

KDM4C inhibition blocks tumor growth in basal breast cancer by promoting cathepsin L-mediated histone H3 cleavage

Project description:KDM4C inhibition blocks tumor growth in basal breast cancer by promoting cathepsin L-mediated histone H3 cleavage

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Gene expresion changes following knockdown of KDM4C in primary fibroblasts

Project description:Epigenetic and genetic regulations are sometimes considered as separate mechanisms that influence gene expression and phenotypes. However, there are DNA sequence variants in epigenetic regulators that could affect gene regulation. The histone demethylase, KDM4C, promotes transcriptional activation by removing the repressive histone mark, tri-methylation of lysine 9 of histone H3 (H3K9me3), from its target genes. In this study, we uncovered cis-acting DNA sequence variants in KDM4C that contribute to individual differences in its expression. Utilizing this natural variation, we performed genetic analyses in B-cells in order to identify target genes that are regulated by KDM4C. We used microarrays to investigate gene expression changes in the target genes from our genetic analyses following knockdown of KDM4C in primary fibroblasts. Primary fibroblasts with stable expression of shRNA targeting KDM4C or a control construct were selected for RNA extraction and hybridization to Affymetrix microarrays. Following selection for stable expression of the shRNA constructs we selected clones expressing 3 non-overlapping constructs targeting KDM4C (shKDM4C) and 2 clones expressing the control construct (shCtr) for analysis by microarray.

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Gene expresion changes following knockdown of KDM4C in primary fibroblasts

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Gene expression profiling of human neuroblastoma cell line BE(2)-C with inducible KDM4C expression

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KDM4C epigenetically regulates and forms a feed-forward loop with ALDH1A3 to maintain gastric cancer stemness

Project description:Gastric cancer (GC) stem cells (GCSCs) are characterized as high level of ALDH activity, however, the mechanisms of maintenance of high ALDH activity and stemness in GCSCs are largely unknown. Here, we report that KDM4C, a H3K9me2/3-demethylase, epigenetically regulates ALDH1A3 by histone demethylation and forms a feed-forward loop with ALDH1A3 to supports GS stemness. Ectopic expression of both KDM4C and ALDH1A3 promotes the properties of GCSCs, including spherogenecity, self-renewal, CD44 expression and ALDH activity; knockdown of anyone abolished the effect of each other. KDM4C directly binds to the promoter of ALDH1A3, leads to histone demethylation, thereby promoting ALDH1A3 transcription. Upregulated ALDH1A3 in turn transcriptionally upregulates KDM4C. Simultaneous inhibition of KDM4C and ALDH1A3 synergistically sensitizes GC sphere-derived cells to traditional chemotherapeutic drugs. The finding that upregulated ALDH1A3 promotes its own transcription via KDM4C-mediated epigenetic modification represents an important feed-forward mechanism for GCSCs to maintain stemness and promote tumourigenesis and our work thus suggests a novel therapeutic strategy for eradicating human GCSCs. To investigate the mechanisms underlying KDM4C promoting CG stemness, we identified the differentially expressed proteins (DEPs) between KDM4C-overexpressing and control AGS cells by iTRAQ-based quantitative proteomic analysis.

2022-02-16 | PXD023455 | Pride

Gene expression profiling of human neuroblastoma cell line BE(2)-C with inducible KDM4C expression

Project description:The microarray gene expression profiling reveals that the histone H3 demethylase KDM4C transcriptionally activates the serine-glycine pathway, stress responses and genes in control of cell-cycle progression. Affymetrix microarray assays were performed according to the manufacturer's directions on total RNA isolated from three independent samples of BE(2)-C_tetoff_KDM4C cells cultured in the presence or absence of doxycycline for 6 days.

2015-12-18 | E-GEOD-65966 | biostudies-arrayexpress

KDM4C silencing inhibits cell migration and enhances radiosensitivity by upregulating CXCL2 in hepatocellular carcinoma

Project description:KDM4C, a histone lysine demethylase, has been proposed to participate in malignant transformation and progression in several types of cancer. However, its roles in hepatocellular carcinoma (HCC) remain poorly understood. In this study, we report that KDM4C protein level is upregulated and KDM4C silencing inhibits cell growth, proliferation and migration in HCC. Furthermore, we provide evidence that depletion of KDM4C leads to defective G2/M checkpoint, increases radiation-induced DNA damage and impairs DNA repair, and enhances radiosensitivity in HCC cells. Using RNA sequencing, we uncover that chemokine CXCL2 is a downstream effector of KDM4C. KDM4C knockdown upregulates the expression of CXCL2 and promotes the secretion of CXCL2 in HCC cells. Importantly, the observed effects caused by KDM4C depletion in HCC cells can be partially rescued by CXCL2 silencing. Thus, our findings demonstrate that KDM4C is involved in the cell migration and radiosensitivity via modulating CXCL2, indicating that KDM4C may be a potential therapeutic target in HCC.

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Wnt-Induced Stabilization of KDM4C Is Required for Wnt/beta-Catenin Target Gene Expression and Tumorigenesis

Project description:Wnt/beta-catenin signaling is essential for stem cell regulation and cancer formation by activation of target genes transcription. For transcriptional activation, the histone around promoters needs to be modified to remove transcriptional repressors; however, the underlying mechanisms remain largely unknown. Here, we report that Wnt signal erases TCF4-associated H3K9me2/me3 by recruitment of KDM4C through β-catenin to activate gene transcription. In the absence of Wnt3a, PKR phosphorylates KDM4C which induces its ubiquitination and degradation. Wnt3a stabilizes KDM4C through inhibition of GSK3-dependent PKR kinase activity. Stabilized KDM4C accumulates in nucleus. Through interaction with β-catenin, KDM4C binds to and demethylates TCF4-associate Histone H3K9 which leads to HP1 removal and transcription activation. KDM4C-dependent H3K9 demethylation is essential for Wnt-induced gene expression and tumorigenesis. Importantly, KDM4C levels directly correlate with Wnt signaling activation in human glioblastomas. These findings demonstrate a pivotal epigenetic regulation mechanism for Wnt/β-catenin signaling activation in tumorigenesis.

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