KDM5A noncanonically binds antagonists MLL1/2 to mediate gene regulation and promotes epithelial to mesenchymal transition

Kirtana, R.; Manna, Soumen; Patra, Samir Kumar

doi:10.1016/j.bbagrm.2023.194986

Cited by 6 publications

(5 citation statements)

References 35 publications

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“…Analyzing the in-silico studies, we understood that both KDM5A and MLL1 are generally expressed in cervical and prostate cancer patients (slightly enhanced though in metastatic prostate tissue samples). Thus, we sort to elucidate how KDM5A and MLL1 regulate the genes involved in key metabolic processes in these cancers by either depleting (using siKDM5A and siMLL1) or overexpressing (SFB-RBP2) these proteins [29] and (supplementary figure S2 ); we further performed quantitative PCR (23 genes) and immunoblotting (4 proteins) of some of the important enzymes involved in glycolysis, TCA cycle, ATP synthesis, PPP and lactate fermentation using HeLa, HaCaT and PC3 cell lines. From our q-PCR study, we understood that KDM5A regulated most of the genes in a demethylase dependent manner in all the 3 cell lines tested proving that these genes were direct targets, hence displayed increased expression in knockdown and were downregulated when KDM5A was overexpressed.…”

Section: Resultsmentioning

confidence: 99%

“…ChIP experiments were performed using our laboratory protocol [27, 29] adapted from Fortschegger et al, 2010 with slight modifications [30]. Following the required treatments, cells were washed with PBS, fixed with 5mL of 1% formaldehyde for 10 minutes on a rocker.…”

Section: Methodsmentioning

confidence: 99%

Section: Supplementary Table T3-t6)mentioning

confidence: 99%

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Modulation of H3K4 trimethylation by KDM5A and MLLs impacts metabolic adaptability in prostate and cervical cancer cells

Kirtana,

Manna,

Patra

2024

Preprint

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Chemical modifications of chromatin modulate gene expression and induce essential metabolic plasticity for tumor growth. Accumulation of H3K4me3 in the promoter of a gene activates transcription by making the promoter accessible to the polymerases. Methylation of H3K4 is catalysed by MLLs and demethylation of H3K4me3 is catalysed by KDM5 family proteins. Herein, we investigated if genes encoding the enzymes involved in glucose metabolism are dependent on KDM5A and MLL1, and if targeting the H3K4me3 would help in modulating the resilience of cancer cells. We present that KDM5A modulates most of the metabolic genes in a demethylase dependent manner as assesses by H3K4me3 occupancy on G6PD and catalase promoters. Targeting its expression would indeed help in sensitizing cancer cells to ROS dependent apoptotic cell death. We elucidated the differences in the epigenetic regulation in cancerous cells originated from cervical and prostate tissues and used a normal skin keratinocyte for comparison. In cervical and prostate cancers - KDM5A activated glycolysis but downregulates other metabolic processes. In cervical cancer, which majorly depends on PPP, changes in KDM5A did not modulate the G6PD expression. Further, we have shown that curcumin treatment enhanced KDM5A expression and downregulated MLL2 in cancer cell lines but not in keratinocyte cells. Curcumin inhibited metabolic pathways and enhanced apoptosis in cancer cells without affecting keratinocyte cells by modulating KDM5A and MLL levels. This work also strengthens the basic concept that, epigenetic modulations of genes in a tissue precisely depends on signal and sites of modification(s).

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Supplementary Table T3-t6)mentioning

confidence: 99%

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Modulation of H3K4 trimethylation by KDM5A and MLLs impacts metabolic adaptability in prostate and cervical cancer cells

Kirtana,

Manna,

Patra

2024

Preprint

Self Cite

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“…When a certain epigenetic modi er expression is targeted by knockdown or overexpression, whether the global changes or gene-speci c expression pattern lay in uence over cell cycle is a question that need addressing. Recently, we have deciphered that KDM5A in association with MLL1/2 regulates expression of genes associated with EMT; where, as repressor of genes KDM5A demethylates H3K4me3 to H3K4me, and activator of gene it does not demethylate H3K4me3 but in association with MLL inhibits histone deacetylase activity [27].…”

Section: Discussionmentioning

confidence: 99%

MLL and KDM5A activity during cell cycle progression depend on Ras signalling

Patra,

Kirtana,

Manna

2024

Preprint

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Cell cycle progression is regulated by many extracellular stimuli and intracellular signaling. Interaction between different epigenetic modifiers and transcription factors regulate the expression of genes encoding proteins involved in cell cycle control. Along with the cyclin-CDK complexes and phosphatases, RAS- signaling play crucial role to direct the cell passage through different stages of cell cycle. In this scenario, chromatin configuration is important for the progression of cell division and chromatin modifications (DNA methylation and histone modifications) helps to attain correct chromatin folds. Here, in this study we analyzed how modulation of H3K4me3 by MLL1 and KDM5A affect cell cycle progression. As slow and fast cycling cell lines exhibited differences in mechanisms of regulation, from in-silico screening and experimental demonstration we deciphered that the expression of the MAPK effector, RAS is involved to controlling the expression and activity of KDM5A and MLL proteins to balance H3K4me3 oscillation throughout cell cycle.

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“…Epigenetic signaling is the biological process that leads to changes in epigenetic marks such as DNA methylation, histone modifications (Kac, Kcr, Klac, etc. ), non-coding RNAs (miRNAs and siRNAs), and chromatin accessibility [ 57 – 60 ]. Functional readouts of histone modifications serve as an important mechanism for epigenetic signaling.…”

Section: Introductionmentioning

confidence: 99%

Unveiling the role of GAS41 in cancer progression

Ji,

Li,

Liu

et al. 2023

Cancer Cell Int

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GAS41, a member of the human YEATS domain family, plays a pivotal role in human cancer development. It serves as a highly promising epigenetic reader, facilitating precise regulation of cell growth and development by recognizing essential histone modifications, including histone acetylation, benzoylation, succinylation, and crotonylation. Functional readouts of these histone modifications often coincide with cancer progression. In addition, GAS41 functions as a novel oncogene, participating in numerous signaling pathways. Here, we summarize the epigenetic functions of GAS41 and its role in the carcinoma progression. Moving forward, elucidating the downstream target oncogenes regulated by GAS41 and the developing small molecule inhibitors based on the distinctive YEATS recognition properties will be pivotal in advancing this research field.

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KDM5A noncanonically binds antagonists MLL1/2 to mediate gene regulation and promotes epithelial to mesenchymal transition

Cited by 6 publications

References 35 publications

Modulation of H3K4 trimethylation by KDM5A and MLLs impacts metabolic adaptability in prostate and cervical cancer cells

Modulation of H3K4 trimethylation by KDM5A and MLLs impacts metabolic adaptability in prostate and cervical cancer cells

MLL and KDM5A activity during cell cycle progression depend on Ras signalling

Unveiling the role of GAS41 in cancer progression

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