The inhibitors of KDM4 and KDM6 histone lysine demethylases enhance the anti-growth effects of erlotinib and HS-173 in head and neck cancer cells

Kleszcz, Robert; Skalski, Marcin; Krajka‐Kuźniak, Violetta; Paluszczak, Jarosław

doi:10.1016/j.ejps.2021.105961

Cited by 18 publications

(24 citation statements)

References 41 publications

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“…Here, we found dysregulation of Hippo after depletion of LEF1 and KDM4A, and noticed that LATS2 regulated multiple downstream targets associated with cell cycle and apoptosis [48,49]. After knockdown of LEF1 or KDM4A, the cell cycle was stalled at the G1 phase [17,50], which may be due to the increased level of LATS2. We suspect that LEF1 recruits KDM4A/N-CoR and may also recruit other epigenetic modi cation complexes to maintain the homeostasis of histone modi cations at target promoters, thereby transcriptionally suppressing tumoursuppressor genes such as LATS2 and inhibiting the progression of OSCC.…”

Section: Discussionmentioning

confidence: 99%

“…LEF1 is associated with histone modi cation and its role in OSCC may depend on different interactions with speci c molecules [28,29]. The KDM4 subfamily of histonemodifying enzymes dysregulated in OSCC comprises four enzymatically activated members: KDM4A, B, C, and D. [17] Thus, we analysed the expression of LEF1 and KDM4s using The Cancer Genome Atlas (TCGA) Head and Neck Cancer dataset. RNA-sequencing (RNA-seq) analysis of 566 samples (44 normal and 522 tumour) suggested that LEF1, KDM4A, and KDM4D were expressed at higher levels in tumour tissues than in normal tissues, whereas KDM4B was expressed at lower levels in tumour tissues (Fig.…”

Section: Upregulation Of Lef1 Is Correlated With Oscc Progressionmentioning

confidence: 99%

“…Histone modi cations play crucial roles in OSCC pathogenesis and progression through gene silencing or activation [14,15]. Histone lysine demethylases (KDMs) play a role in transcriptional regulation by affecting the methylation of H3K4, H3K9, H3K27, and H3K36, which may lead to changes in the expression of tumour-suppressor genes and proto-oncogenes [16][17][18][19]. KDM4A (also known as JMJD2A) is a member of the KDM family that represses or activates genes via its function as a demethylase or recruits chromatin factors [20,21].…”

Section: Introductionmentioning

confidence: 99%

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Carcinogenesis promotion in oral squamous cell carcinoma: KDM4A complex-mediated gene transcriptional suppression by LEF1

Hou¹,

et al. 2023

Preprint

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Oral squamous cell carcinoma (OSCC) is the most prevalent cancer of the mouth, characterised by rapid progression and poor prognosis. Hence, there is an urgent need to develop predictive targets for early diagnosis, prognosis determination, and clinical therapy. Dysregulation of lymphoid enhancer-binding factor 1 (LEF1), an important transcription factor involved in the Wnt-β-catenin pathway, contributes to poor prognosis of OSCC. Herein, we explored the correlation of LEF1 with Histone lysine demethylase 4A (KDM4A). We confirmed that the KDM4A complex was recruited by LEF1 and specifically bound to the promoter region of LATS2, thereby inhibiting its expression, and consequently promoting cell proliferation and impeding apoptosis in OSCC. Lastly, we established NOD/SCID mouse xenograft models using CAL-27 cells to conduct an in vivo analysis of the roles of LEF1 and KDM4A in tumour growth. Overall, the results of this study demonstrate that LEF1 plays a pivotal role in OSCC development and has potential to serve as a target for early diagnosis and treatment of OSCC.

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Section: Discussionmentioning

confidence: 99%

Section: Upregulation Of Lef1 Is Correlated With Oscc Progressionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Carcinogenesis promotion in oral squamous cell carcinoma: KDM4A complex-mediated gene transcriptional suppression by LEF1

Hou¹,

et al. 2023

Preprint

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“…Other cancer types harboring SVs in KDM4C were renal, head and neck, ovarian, hepatocarcinoma, esophageal, bladder, prostate, osteosarcoma, and gastric cancer, suggesting that KDM4C alterations might not be restricted to lymphomas. A role of KDM4C in these tumors has been discussed previously [38][39][40][41][42][43][44][45] .…”

Section: Genomic Alterations Affecting the Kdm4c Gene Locusmentioning

confidence: 91%

Focal structural variants revealed by whole genome sequencing disrupt the histone demethylase KDM4C in B-cell lymphomas

et al. 2022

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Histone methylation-modifiers, such as EZH2 and KMT2D, are recurrently altered in B-cell lymphomas. To comprehensively describe the landscape of alterations affecting genes encoding histone methylation-modifiers in lymphomagenesis we investigated whole genome and transcriptome data of 186 mature B-cell lymphomas sequenced in the ICGC MMML-Seq project. Besides confirming common alterations of KMT2D (47% of cases), EZH2 (17%), SETD1B (5%), PRDM9 (4%), KMT2C (4%), and SETD2 (4%), also identified by prior exome or RNA-sequencing studies, we here found recurrent alterations to KDM4C in chromosome 9p24, encoding a histone demethylase. Focal structural variation was the main mechanism of KDM4C alterations, and was independent from 9p24 amplification. We also identified KDM4C alterations in lymphoma cell lines including a focal homozygous deletion in a classical Hodgkin lymphoma cell line. By integrating RNA-sequencing and genome sequencing data we predict that KDM4C structural variants result in loss-offunction. By functional reconstitution studies in cell lines, we provide evidence that KDM4C can act as a tumor suppressor. Thus, we show that identification of structural variants in whole genome sequencing data adds to the comprehensive description of the mutational landscape of lymphomas and, moreover, establish KDM4C as a putative tumor suppressive gene recurrently altered in subsets of B-cell derived lymphomas.

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“…Experimental data demonstrated that HS-173 could inhibit the proliferation of human non-small cell lung cancer (NSCLC) cells, human Hep3B hepatoma, and human SkBr3 breast cancer cells through the induction of G2/M phase cell cycle arrest and apoptosis [ 8 , 9 ]. Moreover, studies have reported that HS-173 could induce cell death in head and neck squamous cell carcinoma (HNSCC) cells [ 10 ], and the effect was enhanced by inhibitors of KDM4 and KDM6 histone lysine demethylases [ 11 ]. Through simultaneous targeting of Raf/MEK/ERK and PI3K/Akt signaling pathways, the synergistic effects of HS-173 with sorafenib against the proliferation of pancreatic cancer cells [ 12 ] and with trametinib against the proliferation of HNSCC cells [ 13 ] have been reported.…”

Section: Introductionmentioning

confidence: 99%

ABCB1 and ABCG2 Overexpression Mediates Resistance to the Phosphatidylinositol 3-Kinase Inhibitor HS-173 in Cancer Cell Lines

Hung

Hsieh

et al. 2023

Cells

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Constitutive activation of the phosphoinositide-3-kinase (PI3K)/Akt signaling pathway is crucial for tumor growth and progression. As such, this pathway has been an enticing target for drug discovery. Although HS-173 is a potent PI3K inhibitor that halts cancer cell proliferation via G2/M cell cycle arrest, the resistance mechanisms to HS-173 have not been investigated. In this study, we investigated the susceptibility of HS-173 to efflux mediated by the multidrug efflux transporters ABCB1 and ABCG2, which are two of the most well-known ATP-binding cassette (ABC) transporters associated with the development of cancer multidrug resistance (MDR). We found that the overexpression of ABCB1 or ABCG2 significantly reduced the efficacy of HS-173 in human cancer cells. Our data show that the intracellular accumulation of HS-173 was substantially reduced by ABCB1 and ABCG2, affecting G2/M arrest and apoptosis induced by HS-173. More importantly, the efficacy of HS-173 in multidrug-resistant cancer cells could be recovered by inhibiting the drug-efflux function of ABCB1 and ABCG2. Taken together, our study has demonstrated that HS-173 is a substrate for both ABCB1 and ABCG2, resulting in decreased intracellular concentration of this drug, which may have implications for its clinical use.

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The inhibitors of KDM4 and KDM6 histone lysine demethylases enhance the anti-growth effects of erlotinib and HS-173 in head and neck cancer cells

Cited by 18 publications

References 41 publications

Carcinogenesis promotion in oral squamous cell carcinoma: KDM4A complex-mediated gene transcriptional suppression by LEF1

Carcinogenesis promotion in oral squamous cell carcinoma: KDM4A complex-mediated gene transcriptional suppression by LEF1

Focal structural variants revealed by whole genome sequencing disrupt the histone demethylase KDM4C in B-cell lymphomas

ABCB1 and ABCG2 Overexpression Mediates Resistance to the Phosphatidylinositol 3-Kinase Inhibitor HS-173 in Cancer Cell Lines

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