Targeting the Senescence-Overriding Cooperative Activity of Structurally Unrelated H3K9 Demethylases in Melanoma

Yu, Yong A.; Schleich, Kolja; Yue, Bin; Ji, Sujuan; Lohneis, Philipp; Kemper, Kristel; Silvis, Mark R.; Qutob, Nouar; Rooijen, Ellen van; Werner-Klein, Melanie; Li, Lianjie; Dhawan, Dhriti; Meierjohann, Svenja; Reimann, Maurice; Elkahloun, Abdel G.; Treitschke, Steffi; Dörken, Bernd; Speck, Christian; Mallette, Frédérick A.; Zon, Leonard I.; Holmen, Sheri L.; Peeper, Daniel S.; Samuels, Yardena; Schmitt, Clemens A.; Lee, Soyoung

doi:10.1016/j.ccell.2018.03.009

Cited by 34 publications

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“…These steps could be attributed to lymphoma cells (through Bcl2 -mediated apoptotic block or Suv39h1 knockout-based senescence incapability) and macrophages (through interference with TGFβ production), respectively, and all led to accelerated lymphoma growth in vivo 121 . As seen in response to p53 and/or p21 reactivation, restoration of melanoma senescence by pharmacological inhibition or genetic inactivation of H3K9me3 demethylases led to the recruitment of macrophages to tumour sites in vivo 149 . In mouse models of aggressive B cell lymphomas harbouring NF-κB-deregulating mutations, activating Myd88 or Card11 mutations accelerated lymphomagenesis despite enforcing OIS in a substantial proportion of Eµ- myc lymphoma cultured cells.…”

Section: Senescence and Tumour Suppressionmentioning

confidence: 96%

“…Besides, senescent cells are metabolically highly active and turn around crucial maintenance factors of the senescence response. For example, they need to renew transcriptionally repressive H3K9me3 marks in the vicinity of E2F target gene promoters caused by nucleosome turnover 149 , 180 . Of note, genetic interference with senescence-essential factors, especially using inducible systems, underscored that, similar to other biological states, senescence is not necessarily irreversible 125 , 126 , 149 .…”

Section: Senescence and Tumour Promotionmentioning

confidence: 99%

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Senescence and cancer — role and therapeutic opportunities

2022

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Cellular senescence is a state of stable, terminal cell cycle arrest associated with various macromolecular changes and a hypersecretory, pro-inflammatory phenotype. Entry of cells into senescence can act as a barrier to tumorigenesis and, thus, could in principle constitute a desired outcome for any anticancer therapy. Paradoxically, studies published in the past decade have demonstrated that, in certain conditions and contexts, malignant and non-malignant cells with lastingly persistent senescence can acquire pro-tumorigenic properties. In this Review, we first discuss the major mechanisms involved in the antitumorigenic functions of senescent cells and then consider the cell-intrinsic and cell-extrinsic factors that participate in their switch towards a tumour-promoting role, providing an overview of major translational and emerging clinical findings. Finally, we comprehensively describe various senolytic and senomorphic therapies and their potential to benefit patients with cancer.

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Section: Senescence and Tumour Suppressionmentioning

confidence: 96%

Section: Senescence and Tumour Promotionmentioning

confidence: 99%

Senescence and cancer — role and therapeutic opportunities

2022

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“…KDM4C was found to be overexpressed in various cancer entities, including leukemia [115]. Inhibition of KDM4C successfully restored senescence and effectively controlled melanoma cell growth in vitro and in vivo [116]. Consistently, genetic knockout of Kdm4c in MLL-AF9 leukemia targets AML cells in vivo, due to decreased interleukin 3 receptor α (IL3rα) subunit expression without disturbing healthy hematopoiesis [117,118].…”

Section: Epigenetic Modifiersmentioning

confidence: 91%

Molecular Mechanisms of Senescence and Implications for the Treatment of Myeloid Malignancies

Ernst

Heidel

2021

Cancers

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Senescence is a cellular state that is involved in aging-associated diseases but may also prohibit the development of pre-cancerous lesions and tumor growth. Senescent cells are actively secreting chemo- and cytokines, and this senescence-associated secretory phenotype (SASP) can contribute to both early anti-tumorigenic and long-term pro-tumorigenic effects. Recently, complex mechanisms of cellular senescence and their influence on cellular processes have been defined in more detail and, therefore, facilitate translational development of targeted therapies. In this review, we aim to discuss major molecular pathways involved in cellular senescence and potential therapeutic strategies, with a specific focus on myeloid malignancies.

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“…Another recent study showed that H3K9 demethylases (which include KDM3B) can disable senescence, allowing ras/braf mutant melanoma development and progression. This was reversed when treated with H3K9 inhibitors in vitro and in vivo ( Yu et al, 2018 ). The main role of KDM6A/B may be as an antagonist of EZH2 which has been implicated in the growth and progression in melanoma.…”

Section: The Function Of Kdms In Normal Development and Deregulation In Cancermentioning

confidence: 99%

Lysine Demethylases: Promising Drug Targets in Melanoma and Other Cancers

2021

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Epigenetic dysregulation has been implicated in a variety of pathological processes including carcinogenesis. A major group of enzymes that influence epigenetic modifications are lysine demethylases (KDMs) also known as “erasers” which remove methyl groups on lysine (K) amino acids of histones. Numerous studies have implicated aberrant lysine demethylase activity in a variety of cancers, including melanoma. This review will focus on the structure, classification and functions of KDMs in normal biology and the current knowledge of how KDMs are deregulated in cancer pathogenesis, emphasizing our interest in melanoma. We highlight the current knowledge gaps of KDMs in melanoma pathobiology and describe opportunities to increases our understanding of their importance in this disease. We summarize the progress of several pre-clinical compounds that inhibit KDMs and represent promising candidates for further investigation in oncology.

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Targeting the Senescence-Overriding Cooperative Activity of Structurally Unrelated H3K9 Demethylases in Melanoma

Cited by 34 publications

References 0 publications

Senescence and cancer — role and therapeutic opportunities

Senescence and cancer — role and therapeutic opportunities

Molecular Mechanisms of Senescence and Implications for the Treatment of Myeloid Malignancies

Lysine Demethylases: Promising Drug Targets in Melanoma and Other Cancers

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