Dysregulation of c-Myb Pathway by Aberrant Expression of Proto-oncogene <i>MYB</i> Provides the Basis for Malignancy in Adult T-cell Leukemia/lymphoma Cells

Nakano, Kazumi; Uchimaru, Kaoru; Utsunomiya, Atae; Yamaguchi, Kazunari; Watanabe, Toshiki

doi:10.1158/1078-0432.ccr-15-1739

Cited by 25 publications

(31 citation statements)

References 52 publications

(57 reference statements)

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“…The well-known transcription factor c-Myb has been studied extensively in solid tumors and blood cell malignancies due to its roles in cell proliferation, differentiation, and survival [47] . However, c-Myb is also intimately associated with cellular metabolism.…”

Section: Discussionmentioning

confidence: 99%

Cysteine Dioxygenase 1 Mediates Erastin-Induced Ferroptosis in Human Gastric Cancer Cells

et al. 2017

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BACKGROUND: Ferroptosis is a recently discovered form of iron-dependent nonapoptotic cell death. It is characterized by loss of the activity of the lipid repair enzyme, glutathione peroxidase 4 (GPX4), and accumulation of lethal reactive lipid oxygen species. However, we still know relatively little about ferroptosis and its molecular mechanism in gastric cancer (GC) cells. Here, we demonstrate that erastin, a classic inducer of ferroptosis, induces this form of cell death in GC cells and that cysteine dioxygenase 1 (CDO1) plays an important role in this process. METHODS: We performed quantitative real-time polymerase chain reaction, Western blotting, cell viability assay, reactive oxygen species (ROS) assay, glutathione assay, lipid peroxidation assay, RNAi and gene transfection, immunofluorescent staining, dual-luciferase reporter assay, transmission electron microscopy, and chromatin immunoprecipitation assay to study the regulation of ferroptosis in GC cells. Mouse xenograft assay was used to figure out the mechanism in vivo. RESULTS: Silencing CDO1 inhibited erastin-induced ferroptosis in GC cells both in vitro and in vivo. Suppression of CDO1 restored cellular GSH levels, prevented ROS generation, and reduced malondialdehyde, one of the end products of lipid peroxidation. In addition, silencing COO1 maintained mitochondrial morphologic stability in erastin-treated cells. Mechanistically, c-Myb transcriptionally regulated CDO1, and inhibition of CDO1 expression upregulated GPX4 expression. CONCLUSIONS: Our findings give a better understanding of ferroptosis and its molecular mechanism in GC cells, gaining insight into ferroptosis-mediated cancer treatment.

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Section: Discussionmentioning

confidence: 99%

Cysteine Dioxygenase 1 Mediates Erastin-Induced Ferroptosis in Human Gastric Cancer Cells

et al. 2017

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“…Along these lines, we failed to detect c-Myb expression in control MF, whereas in TAMs c-Myb was detected at the RNA level and in nuclear extracts at the protein level. c-Myb contributes to the development of leukemia (50) and several solid tumors, and previous works predominantly focused on c-Myb in cancer cells (51,52). The role of c-Myb within cells of the TME has not yet been adequately addressed.…”

Section: Discussionmentioning

confidence: 99%

Apoptotic Cancer Cells Suppress 5-Lipoxygenase in Tumor-Associated Macrophages

Ringleb

Strack

Angioni

et al. 2018

The Journal of Immunology

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The enzyme 5-lipoxygenase (5-LO) is key in the synthesis of leukotrienes, which are potent proinflammatory lipid mediators involved in chronic inflammatory diseases including cancer. 5-LO is expressed in immune cells but also found in cancer cells. Although the role of 5-LO in tumor cells is beginning to emerge, with the notion that tumor-promoting functions are attributed to its products, the function of 5-LO in the tumor microenvironment remains unclear. To understand the role of 5-LO and its products in the tumor microenvironment, we analyzed its expression and function in tumor-associated macrophages (TAMs). TAMs were generated by coculturing primary human macrophages (MΦ) with human MCF-7 breast carcinoma cells, which caused cell death of cancer cells followed by phagocytosis of cell debris by MΦ. Expression and activity of 5-LO in TAMs were reduced upon coculture with cancer cells. Downregulation of 5-LO in TAMs required tumor cell death and the direct contact between MΦ and dying cancer cells via Mer tyrosine kinase. Subsequently, upregulation of proto-oncogene c-Myb in TAMs induced a stable transcriptional repression of 5-LO. Reduced 5-LO expression in TAMs was mechanistically coupled to an attenuated T cell recruitment. In primary TAMs from human and murine breast tumors, 5-LO expression was absent or low when compared with monocyte-derived MΦ. Our data reveal that 5-LO, which is required for leukotriene production and subsequent T cell recruitment, is downregulated in TAMs through Mer tyrosine kinase-dependent recognition of apoptotic cancer cells. Mechanistically, we noticed transcriptional repression of 5-LO by proto-oncogene c-Myb and conclude that loss of stromal 5-LO expression favors tumor progression.

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“…The aberrant expression of MYB was also identified in colon carcinoma, 29 pancreatic cancer, 11 and acute leukemia. 13,14 Furthermore, the overexpression of MYB is correlated with poor prognosis of colorectal cancer. 30 On the contrary, some studies also indicated that MYB might have tumorsuppressor role in cancer.…”

Section: Discussionmentioning

confidence: 99%

PML/RARa blocks the differentiation and promotes the proliferation of acute promyelocytic leukemia through activating MYB expression by transcriptional and epigenetic regulation mechanisms

Wang

Tian

et al. 2018

J of Cellular Biochemistry

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The promyelocytic leukemia (PML)/retinoic acid receptor‐alpha (RARα) onco‐fusion protein that is generated from t(15;17) chromosome translocation is crucial for the leukemogenesis of acute promyelocytic leukemia (APL) and is well documented as a transcriptional repressor. To understand the relationship between PML/RARα and the oncogene in the development of APL, we investigate the regulation mechanism of PML/RARα to MYB proto‐oncogene and the role of this regulation on the proliferation and differentiation of APL cells. Reverse transcription‐quantitative polymerase chain reaction (RT‐qPCR) assays show that MYB expression was significantly higher in PML/RARα positive cell lines. Microarray data verify that the MYB expression was significantly higher in APL patient samples than in normal promyelocyte samples. Further expression analysis from RT‐qPCR and microarray data verifies that the expression of MYB is upregulated by PML/RARα. Transcriptional factor binding analysis shows that MYB is directly bound by PML/RARα and its cofactors. Luciferase assays show that PML/RARα transactivated MYB promoter activity through the RARα binding site and the coexistence of CCAAT enhancer binding protein ε. We also find that PML/RARα increases the acetylation level of the promoter region of MYB. Further evidence demonstrates that PML/RARα regulates MYB expression through long‐range interaction. Functionally, PML/RARα increases the cell proliferation and blocks the differentiation through activating MYB expression. Collectively, this study uncovers a novel mechanism of PML/RARα‐mediated transcriptional activation and enriches our knowledge of the onco‐fusion protein‐mediated transcription activation.

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Dysregulation of c-Myb Pathway by Aberrant Expression of Proto-oncogene MYB Provides the Basis for Malignancy in Adult T-cell Leukemia/lymphoma Cells

Cited by 25 publications

References 52 publications

Cysteine Dioxygenase 1 Mediates Erastin-Induced Ferroptosis in Human Gastric Cancer Cells

Cysteine Dioxygenase 1 Mediates Erastin-Induced Ferroptosis in Human Gastric Cancer Cells

Apoptotic Cancer Cells Suppress 5-Lipoxygenase in Tumor-Associated Macrophages

PML/RARa blocks the differentiation and promotes the proliferation of acute promyelocytic leukemia through activating MYB expression by transcriptional and epigenetic regulation mechanisms

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