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.2018.01.002

Cited by 123 publications

(120 citation statements)

References 69 publications

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“…Importantly, miR‐24‐2‐dependent miR‐6079 increased the level of tri‐methylation of histone lysine (H3K9me3) by inhibiting of JMJD2A. Studies have reported that H3K9me3 modification in the promoter region of the gene can affect the transcriptional activity of some genes . Our results also confirmed that miR‐24‐2 increased the H3K9me3 loading on the oncogene pim 1 promoter region, thereby promoting the expression of Pim1, indicating that the change of H3K9me3 modification triggered by miR‐24‐2 is beneficial to the growth of cancer cells at least in hepatoma cell Hep3B.…”

Section: Discussionsupporting

confidence: 81%

miR24‐2 accelerates progression of liver cancer cells by activating Pim1 through tri‐methylation of Histone H3 on the ninth lysine

Yang

Song

Meng

et al. 2020

J Cellular Molecular Medi

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Several microRNAs are associated with carcinogenesis and tumour progression. Herein, our observations suggest both miR24‐2 and Pim1 are up‐regulated in human liver cancers, and miR24‐2 accelerates growth of liver cancer cells in vitro and in vivo. Mechanistically, miR24‐2 increases the expression of N6‐adenosine‐methyltransferase METTL3 and thereafter promotes the expression of miR6079 via RNA methylation modification. Furthermore, miR6079 targets JMJD2A and then increased the tri‐methylation of histone H3 on the ninth lysine (H3K9me3). Therefore, miR24‐2 inhibits JMJD2A by increasing miR6079 and then increases H3K9me3. Strikingly, miR24‐2 increases the expression of Pim1 dependent on H3K9me3 and METTL3. Notably, our findings suggest that miR24‐2 alters several related genes (pHistone H3, SUZ12, SUV39H1, Nanog, MEKK4, pTyr) and accelerates progression of liver cancer cells through Pim1 activation. In particular, Pim1 is required for the oncogenic action of miR24‐2 in liver cancer. This study elucidates a novel mechanism for miR24‐2 in liver cancer and suggests that miR24‐2 may be used as novel therapeutic targets of liver cancer.

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Section: Discussionsupporting

confidence: 81%

miR24‐2 accelerates progression of liver cancer cells by activating Pim1 through tri‐methylation of Histone H3 on the ninth lysine

Yang

Song

Meng

et al. 2020

J Cellular Molecular Medi

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“…5a, b). Furthermore, p16 INK4A , a critical OIS tumor suppressor and senescence mediator, and H3K9me3, a marker of senescence-associated heterochromatic foci 28,29 . Both of them were significantly repressed by the absence of Men1 in both KMS and Men1 Δ/Δ mice (Fig.…”

Section: Loss Of Menin Triggers Aberrant Dna Damage Responsementioning

confidence: 99%

“…7b). 2-PCPA-1a, an inhibitor of LSD1, promotes oncogenic BRAF mutation-induced OIS in melanoma cells 29 . IR exposure elicited obvious SA-β-gal staining in IMR-90 cells (51.9%) that was eliminated by MI-3 (30.0%) but markedly increased by exposure to SP2509 (95.4%) ( Supplementary Fig.…”

Section: Lsd1 Inhibitor Reverses Ne Differentiation In Lung Cancersmentioning

confidence: 99%

MEN1 deficiency leads to neuroendocrine differentiation of lung cancer and disrupts the DNA damage response

et al. 2020

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The MEN1 gene, a tumor suppressor gene that encodes the protein menin, is mutated at high frequencies in neuroendocrine (NE) tumors; however, the biological importance of this gene in NE-type lung cancer in vivo remains unclear. Here, we established an ATII-specific Kras G12D/+ /Men1 −/− driven genetically engineered mouse model and show that deficiency of menin results in the accumulation of DNA damage and antagonizes oncogenic Kras-induced senescence and the epithelial-to-mesenchymal transition during lung tumorigenesis. The loss of menin expression in certain human primary lung cancers correlates with elevated NE profiles and reduced overall survival.

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“…and PTPN6 have been shown to regulate CS in human cell lines, and will be added to build 2 of CellAge (Sun et al, 2015;Yu et al, 2018).…”

Section: Unweighted Rna-seq Co-expression Networkmentioning

confidence: 99%

A Multidimensional Systems Biology Analysis of Cellular Senescence in Ageing and Disease

Avelar

Ortega

Tăcutu

et al. 2019

Preprint

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Cellular senescence, a permanent state of replicative arrest in otherwise proliferating cells, is a hallmark of ageing and has been linked to ageing-related diseases like cancer. Senescent cells have been shown to accumulate in tissues of aged organisms which in turn can lead to chronic inflammation. Many genes have been associated with cell senescence, yet a comprehensive understanding of cell senescence pathways is still lacking. To this end, we created CellAge (http://genomics.senescence.info/cells), a manually curated database of 279 human genes associated with cellular senescence, and performed various integrative and functional analyses. We observed that genes promoting cell senescence tend to be overexpressed with age in human tissues and are also significantly overrepresented in anti-longevity and tumour-suppressor gene databases.By contrast, genes inhibiting cell senescence overlapped with pro-longevity genes and oncogenes.Furthermore, an evolutionary analysis revealed a strong conservation of senescence-associated genes in mammals, but not in invertebrates. Using the CellAge genes as seed nodes, we also built protein-protein interaction and co-expression networks. Clusters in the networks were enriched for cell cycle and immunological processes. Network topological parameters also revealed novel potential senescence-associated regulators. We then used siRNAs and observed that of 26 candidates tested, 19 induced markers of senescence. Overall, our work provides a new resource for researchers to study cell senescence and our systems biology analyses provide new insights and novel genes regarding cell senescence.

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

Cited by 123 publications

References 69 publications

miR24‐2 accelerates progression of liver cancer cells by activating Pim1 through tri‐methylation of Histone H3 on the ninth lysine

miR24‐2 accelerates progression of liver cancer cells by activating Pim1 through tri‐methylation of Histone H3 on the ninth lysine

MEN1 deficiency leads to neuroendocrine differentiation of lung cancer and disrupts the DNA damage response

A Multidimensional Systems Biology Analysis of Cellular Senescence in Ageing and Disease

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