p53-Independent Effects of Set7/9 Lysine Methyltransferase on Metabolism of Non-Small Cell Lung Cancer Cells

Daks, Alexandra; Shuvalov, Oleg; Fedorova, Olga; Petukhov, Alexey; Lezina, Larissa; Zharova, Arsenia; Baidyuk, E. V.; Khudiakov, Aleksandr; Barlev, Nickolai A.

doi:10.3389/fonc.2021.706668

Cited by 8 publications

(6 citation statements)

References 61 publications

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“…In line with this, we have recently showed that the genetic suppression of Set7/9 has led to the upregulation and activation of Hif1a and its target glycolytic genes even under normoxic conditions. Set7/9 inhibition increased the level of glycolysis and subsequent reduction of ROS accumulation in human lung cancer cells [107]. Thus, collectively, it can be concluded that Set7/9 antagonizes Hif1 activity both under normoxic and hypoxic conditions.…”

Section: Set7/9 and Ros/hif1a Pathwaymentioning

confidence: 78%

Methyltransferase Set7/9 as a Multifaceted Regulator of ROS Response

Daks¹,

Shuvalov²,

Parfenyev³

et al. 2023

Int. J. Biol. Sci.

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Reactive oxygen species (ROS) induce multiple signaling cascades in the cell and hence play an important role in the regulation of the cell's fate. ROS can cause irreversible damage to DNA and proteins resulting in cell death. Therefore, finely tuned regulatory mechanisms exist in evolutionarily diverse organisms that are aimed at the neutralization of ROS and its consequences with respect to cellular damage. The SET domain-containing lysine methyltransferase Set7/9 (KMT7, SETD7, SET7, SET9) post-translationally modifies several histones and non-histone proteins via monomethylation of the target lysines in a sequence-specific manner. In cellulo, the Set7/9-directed covalent modification of its substrates affects gene expression, cell cycle, energy metabolism, apoptosis, ROS, and DNA damage response. However, the in vivo role of Set7/9 remains enigmatic. In this review, we summarize the currently available information regarding the role of methyltransferase Set7/9 in the regulation of ROS-inducible molecular cascades in response to oxidative stress. We also highlight the in vivo importance of Set7/9 in ROS-related diseases.

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Section: Set7/9 and Ros/hif1a Pathwaymentioning

confidence: 78%

Methyltransferase Set7/9 as a Multifaceted Regulator of ROS Response

Daks¹,

Shuvalov²,

Parfenyev³

et al. 2023

Int. J. Biol. Sci.

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“…Different oncogenes and oncosupressors have a critical impact on these metabolic pathways [ 20 , 40 , 46 , 47 , 75 , 76 ]. Transcription factors c-Myc and ATF4 are two master-regulators of glycolysis, respiration, and one-carbon metabolism [ 44 , 45 , 46 , 49 ].…”

Section: Discussionmentioning

confidence: 99%

20-Hydroxyecdysone Confers Antioxidant and Antineoplastic Properties in Human Non-Small Cell Lung Cancer Cells

Shuvalov,

Kirdeeva,

Fefilova

et al. 2023

Metabolites

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20-Hydroxyecdysone (20E) is an arthropod hormone which is synthesized by some plants as part of their defense mechanism. In humans, 20E has no hormonal activity but possesses a number of beneficial pharmacological properties including anabolic, adaptogenic, hypoglycemic, and antioxidant properties, as well as cardio-, hepato-, and neuroprotective features. Recent studies have shown that 20E may also possess antineoplastic activity. In the present study, we reveal the anticancer properties of 20E in Non-Small Cell Lung Cancer (NSCLC) cell lines. 20E displayed significant antioxidant capacities and induced the expression of antioxidative stress response genes. The RNA-seq analysis of 20E-treated lung cancer cells revealed the attenuation of genes involved in different metabolic processes. Indeed, 20E suppressed several enzymes of glycolysis and one-carbon metabolism, as well as their key transcriptional regulators—c-Myc and ATF4, respectively. Accordingly, using the SeaHorse energy profiling approach, we observed the inhibition of glycolysis and respiration mediated by 20E treatment. Furthermore, 20E sensibilized lung cancer cells to metabolic inhibitors and markedly suppressed the expression of Cancer Stem Cells (CSCs) markers. Thus, in addition to the known beneficial pharmacological activities of 20E, our data uncovered novel antineoplastic properties of 20E in NSCLC cells.

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“…However, along with p53 positive regulation, Set7/9 was shown to interact with and stabilize the main p53 negative regulator, Mdm2, under genotoxic conditions [ 104 ]. Moreover, our research group recently demonstrated that Set7/9 acts as a suppressor of metabolic functions of c-Myc thereby participating in the regulation of glycolysis in lung cancer cells [ 105 ]. Given that glycolysis is critical for the maintenance of stem cells [ 106 ] and Set7/9 attenuates the expression of c-Myc, the key glycolytic transcription factor, makes it plausible that Set7/9 regulates stem cells via controlling the p53-c-Myc crosstalk (Fig.…”

Section: Stemness-associated Non-histone Targets Of Set7/9mentioning

confidence: 99%

Lysine-specific methyltransferase Set7/9 in stemness, differentiation, and development

Daks,

Parfenyev,

Shuvalov

et al. 2024

Biol Direct

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The enzymes performing protein post-translational modifications (PTMs) form a critical post-translational regulatory circuitry that orchestrates literally all cellular processes in the organism. In particular, the balance between cellular stemness and differentiation is crucial for the development of multicellular organisms. Importantly, the fine-tuning of this balance on the genetic level is largely mediated by specific PTMs of histones including lysine methylation. Lysine methylation is carried out by special enzymes (lysine methyltransferases) that transfer the methyl group from S-adenosyl-L-methionine to the lysine residues of protein substrates. Set7/9 is one of the exemplary protein methyltransferases that however, has not been fully studied yet. It was originally discovered as histone H3 lysine 4-specific methyltransferase, which later was shown to methylate a number of non-histone proteins that are crucial regulators of stemness and differentiation, including p53, pRb, YAP, DNMT1, SOX2, FOXO3, and others. In this review we summarize the information available to date on the role of Set7/9 in cellular differentiation and tissue development during embryogenesis and in adult organisms. Finally, we highlight and discuss the role of Set7/9 in pathological processes associated with aberrant cellular differentiation and self-renewal, including the formation of cancer stem cells.

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p53-Independent Effects of Set7/9 Lysine Methyltransferase on Metabolism of Non-Small Cell Lung Cancer Cells

Cited by 8 publications

References 61 publications

Methyltransferase Set7/9 as a Multifaceted Regulator of ROS Response

Methyltransferase Set7/9 as a Multifaceted Regulator of ROS Response

20-Hydroxyecdysone Confers Antioxidant and Antineoplastic Properties in Human Non-Small Cell Lung Cancer Cells

Lysine-specific methyltransferase Set7/9 in stemness, differentiation, and development

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