title: Hbo1 is a cyclin E/CDK2 substrate that enriches breast cancer stem-like cells.
abstract: Expression of cyclin E proteolytic cleavage products, low-molecular weight cyclin E (LMW-E), is associated with poor clinical outcome in patients with breast cancer and it enhances tumorigenecity in mouse models. Here we report that LMW-E expression in human mammary epithelial cells induces an epithelial-to-mesenchymal transition phenotype, increases the CD44(hi)/CD24(lo) population, enhances mammosphere formation, and upregulates aldehyde dehydrogenase expression and activity. We also report that breast tumors expressing LMW-E have a higher proportion of CD44(hi)/CD24(lo) tumor cells as compared with tumors expressing only full-length cyclin E. In order to explore how LMW-E enriches cancer stem cells in breast tumors, we conducted a protein microarray analysis that identified the histone acetyltransferase (HAT) Hbo1 as a novel cyclin E/CDK2 substrate. The LMW-E/CDK2 complex phosphorylated Hbo1 at T88 without affecting its HAT activity. When coexpressed with LMW-E/CDK2, wild-type Hbo1 promoted enrichment of cancer stem-like cells (CSC), whereas the T88 Hbo1 mutant reversed the CSC phenotype. Finally, doxorubicin and salinomycin (a CSC-selective cytotoxic agent) synergized to kill cells expressing LMW-E, but not full-length cyclin E. Collectively, our results suggest that the heightened oncogenecity of LMW-E relates to its ability to promote CSC properties, supporting the design of therapeutic strategies to target this unique function.
authors: Departments of Experimental Radiation Oncology, Radiation Oncology, and Surgical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 0066, Houston, TX77030, USA.
authors: Mylinh T
authors: MT
authors: Duong
authors: Said
authors: S
authors: Akli
authors: Sira
authors: S
authors: Macalou
authors: Anna
authors: A
authors: Biernacka
authors: Bisrat G
authors: BG
authors: Debeb
authors: Min
authors: M
authors: Yi
authors: Kelly K
authors: KK
authors: Hunt
authors: Khandan
authors: K
authors: Keyomarsi
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D051927:CD24 Antigen / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism*; D051357:Cyclin-Dependent Kinase 2 / Q000235:genetics / Q000378:metabolism*; D004317:Doxorubicin / Q000494:pharmacology; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism; D047468:Immunoprecipitation; D008970:Molecular Weight; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D040081:Protein Array Analysis; D011714:Pyrans / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D000095662:Polyether Polyketides
chemical_list: D000900:Anti-Bacterial Agents; D000903:Antibiotics, Antineoplastic; D051927:CD24 Antigen; D019927:Cyclin E; D051357:Cyclin-Dependent Kinase 2; D004317:Doxorubicin; D051548:Histone Acetyltransferases; D018960:Hyaluronan Receptors; D011714:Pyrans; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C010327:salinomycin; D000095662:Polyether Polyketides; C496553:KAT7 protein, human; C495894:CDK2 protein, human
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