MOZ (MYST3, KAT6A) inhibits senescence via the INK4A-ARF pathway

Sheikh, Bilal N.; Phipson, Belinda; El-Saafin, Farrah; Vanyai, Hannah K.; Downer, Natalie L.; Bird, Matthew; Kueh, Andrew J.; May, Rose E.; Smyth, Gordon K.; Voss, Anne K.; Thomas, Tim

doi:10.1038/onc.2015.33

Cited by 69 publications

(55 citation statements)

References 76 publications

(77 reference statements)

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“…Moreover, the MOZ and MORF genes have both been identified as top-ranking targets amplified in different types of cancer [102]. Mouse studies indicate that Moz is required for lymphoma development induced by Myc [68] and its loss leads to senescence of mouse embryonic fibroblasts and neural stem cells [70,71]. All of these support that MOZ has an oncogenic role.…”

Section: Moz and Morf In Leukemia Solid Tumors And Developmental Dismentioning

confidence: 94%

“…Moreover, the mouse Moz gene is required for normal B cell development, as well as for optimal lymphoma development induced by Myc [68,69]. In addition, loss of Moz leads to senescence of mouse embryonic fibroblasts and neural stem cells [70,71]. The requirement for lymphoma development and cell proliferation suggests that Moz has an oncogenic role.…”

Section: Moz and Morf In Vertebrate Developmentmentioning

confidence: 97%

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MOZ and MORF acetyltransferases: Molecular interaction, animal development and human disease

Yang

2015

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

101

128

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Lysine residues are subject to many forms of covalent modification and one such modification is acetylation of the ε-amino group. Initially identified on histone proteins in the 1960s, lysine acetylation is now considered as an important form of post-translational modification that rivals phosphorylation. However, only about a dozen of human lysine acetyltransferases have been identified. Among them are MOZ (monocytic leukemia zinc finger protein; a.k.a. MYST3 and KAT6A) and its paralog MORF (a.k.a. MYST4 and KAT6B). Although there is a distantly related protein in Drosophila and sea urchin, these two enzymes are vertebrate-specific. They form tetrameric complexes with BRPF1 (bromodomain- and PHD finger-containing protein 1) and two small non-catalytic subunits. These two acetyltransferases and BRPF1 play key roles in various developmental processes; for example, they are important for development of hematopoietic and neural stem cells. The human KAT6A and KAT6B genes are recurrently mutated in leukemia, non-hematologic malignancies, and multiple developmental disorders displaying intellectual disability and various other abnormalities. In addition, the BRPF1 gene is mutated in childhood leukemia and adult medulloblastoma. Therefore, these two acetyltransferases and their partner BRPF1 are important in animal development and human disease.

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Section: Moz and Morf In Leukemia Solid Tumors And Developmental Dismentioning

confidence: 94%

Section: Moz and Morf In Vertebrate Developmentmentioning

confidence: 97%

MOZ and MORF acetyltransferases: Molecular interaction, animal development and human disease

Yang

2015

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

101

128

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“…2) (41)(42)(43)(44). While MOZ acetylates H3K14 in vitro and is important for the H3K9ac levels at several target genes, the global levels of H3K9ac and H3K14ac are not affected in the absence of MOZ, indicating that other HATs can compensate for the loss of MOZ-mediated histone acetylation (25,42,45). Similarly, the loss of Sas3 does not affect global H3K9ac and -K14ac levels, but disrupting the HAT activity of Sas3 led to decreased levels of H3K9ac and -K14ac in the absence of a HAT in the GNAT family, Gcn5 (3).…”

Section: Enzymatic Specificities and Activities Of Kat6 Hatsmentioning

confidence: 99%

“…On the other hand, MOZ is important for the expression of several repressors of the INK4A/ ARF locus by maintaining the H3K9ac levels at those genes. Therefore, it plays a role in suppressing INKA/ARF-dependent senescence (45,55). As ARF activates the function of p53, MOZ may act as a fine-tuning regulator of the ARF-p53 pathway in senescence through acetylating p53 or H3K9.…”

Section: Roles Of Kat6 Hats In Cell Cycle Regulation and Stem Cell Mamentioning

confidence: 99%

Regulation of KAT6 Acetyltransferases and Their Roles in Cell Cycle Progression, Stem Cell Maintenance, and Human Disease

Huang

Abmayr

Workman

2016

Molecular and Cellular Biology

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The lysine acetyltransferase 6 (KAT6) histone acetyltransferase (HAT) complexes are highly conserved from yeast to higher organisms. They acetylate histone H3 and other nonhistone substrates and are involved in cell cycle regulation and stem cell maintenance. In addition, the human KAT6 HATs are recurrently mutated in leukemia and solid tumors. Therefore, it is important to understand the mechanisms underlying the regulation of KAT6 HATs and their roles in cell cycle progression. In this minireview, we summarize the identification and analysis of the KAT6 complexes and discuss the regulatory mechanisms governing their enzymatic activities and substrate specificities. We further focus on the roles of KAT6 HATs in regulating cell proliferation and stem cell maintenance and review recent insights that aid in understanding their involvement in human diseases.

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“…MOZ was recently shown to induce CDC6 expression and consequently repress the INK4/ARF pathway. 9 Importantly, the development of small molecule inhibitors of MOZ is currently under way. 10 In summary, our paper by Gamell et al describes a novel regulatory pathway that provides a molecular explanation for the loss of the tumor suppressor p16 in adenocarcinoma, the most common sub-type of lung cancer.…”

mentioning

confidence: 99%

Uncovering a novel pathway for p16 silencing: Therapeutic implications for lung cancer

Gamell

Gulati

Solomon

et al. 2017

Molecular & Cellular Oncology

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A key step during onset of most cases of non-small cell lung cancer (NSCLC) is the loss of the tumor suppressor p16 INK4a (best known as p16), commonly due to promoter hypermethylation. We recently reported a novel regulatory pathway involving E6-associated protein and cell division control protein 6, which provides a methylation-independent mechanism for p16 silencing in patients with a particularly aggressive form of NSCLC. CommentaryNon-small cell lung cancer (NSCLC), constituting 80% of all lung cancers, is the leading cause of cancer-related mortality worldwide. Despite important advances in treatment, the disease is rarely curable and prognosis is poor, with a dismal overall 5-year survival rate of only 20%. This highlights the importance of enhancing our knowledge of the underlying molecular events of NSCLC to develop rationally designed methods for early detection and prevention, as well as to discover novel therapeutics approaches for treatment of this disease.The most common genetic event leading to NSCLC is loss of the tumor suppressor p16 INK4a (best known as p16), occurring in »70% of patients. P16, together with the key tumor suppressors p14 ARF and p15 INK4b , is encoded in the INK4/ARF locus, one of the genomic regions most commonly affected in human cancers. Consistent with the role of p16 as a tumor suppressor, low p16 levels are associated with poor prognosis and therapeutic resistance of NSCLC patients. Understanding the mechanisms leading to p16 loss in NSCLC is central to restoring its tumor suppression and improve patient prognosis. Several mechanisms have been defined to explain the loss of p16 in NSCLC: epigenetic silencing of the entire INK4/ARF locus, genetic deletions and mutation of the gene encoding p16 (CDKN2A), and CDKN2A promoter hypermethylation; this last mode being the most common (»37% of the patients) (Fig. 1). Together, these account for the loss of p16 in two-thirds of NSCLC cases, but the molecular explanation for the remaining cases is unknown. In our recent study published in Science Signaling we addressed, at least in part, this gap in knowledge. 1 We unraveled a novel mechanism for the reduction of p16, involving the E3 ubiquitin ligase and transcriptional cofactor, E6-associated protein (E6AP), which we found to be lowly expressed in certain NSCLCs.Our analysis identified E6AP as a positive regulator of the INK4/ARF locus. Mechanistically, we showed that E6AP controls this locus by reducing the ability of E2F transcription factor 1 (E2F1) to bind to the cell division control protein 6 (CDC6) promoter. CDC6 is a repressor of the INK4/ARF locus, and consequently low E6AP levels relieve this repression by CDC6 (Fig. 1). The extent by which E2F1 activity was inhibited by E6AP was comparable to that achieved by retinoblastoma protein (RB1, best known as pRb), the key inhibitor of E2F1 during the cell cycle. However, this action of E6AP is independent of pRb.We demonstrated the clinical relevance of the E6AP-CDC6-p16 axis by analyzing NSCLC human samples. This an...

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MOZ (MYST3, KAT6A) inhibits senescence via the INK4A-ARF pathway

Cited by 69 publications

References 76 publications

MOZ and MORF acetyltransferases: Molecular interaction, animal development and human disease

MOZ and MORF acetyltransferases: Molecular interaction, animal development and human disease

Regulation of KAT6 Acetyltransferases and Their Roles in Cell Cycle Progression, Stem Cell Maintenance, and Human Disease

Uncovering a novel pathway for p16 silencing: Therapeutic implications for lung cancer

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