title: Hypoxia-inducible factor-1α (HIF-1α) promotes cap-dependent translation of selective mRNAs through up-regulating initiation factor eIF4E1 in breast cancer cells under hypoxia conditions.
abstract: Hypoxia promotes tumor evolution and metastasis, and hypoxia-inducible factor-1α (HIF-1α) is a key regulator of hypoxia-related cellular processes in cancer. The eIF4E translation initiation factors, eIF4E1, eIF4E2, and eIF4E3, are essential for translation initiation. However, whether and how HIF-1α affects cap-dependent translation through eIF4Es in hypoxic cancer cells has been unknown. Here, we report that HIF-1α promoted cap-dependent translation of selective mRNAs through up-regulation of eIF4E1 in hypoxic breast cancer cells. Hypoxia-promoted breast cancer tumorsphere growth was HIF-1α-dependent. We found that eIF4E1, not eIF4E2 or eIF4E3, is the dominant eIF4E family member in breast cancer cells under both normoxia and hypoxia conditions. eIF4E3 expression was largely sequestered in breast cancer cells at normoxia and hypoxia. Hypoxia up-regulated the expression of eIF4E1 and eIF4E2, but only eIF4E1 expression was HIF-1α-dependent. In hypoxic cancer cells, HIF-1α-up-regulated eIF4E1 enhanced cap-dependent translation of a subset of mRNAs encoding proteins important for breast cancer cell mammosphere growth. In searching for correlations, we discovered that human eIF4E1 promoter harbors multiple potential hypoxia response elements. Furthermore, using chromatin immunoprecipitation (ChIP) and luciferase and point mutation assays, we found that HIF-1α utilized hypoxia response elements in the human eIF4E1 proximal promoter region to activate eIF4E1 expression. Our study suggests that HIF-1α promotes cap-dependent translation of selective mRNAs through up-regulating eIF4E1, which contributes to tumorsphere growth of breast cancer cells at hypoxia. The data shown provide new insights into protein synthesis mechanisms in cancer cells at low oxygen levels.
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Tingfang
authors.initials: T
authors.lastname: Yi
authors.forename: Evangelos
authors.initials: E
authors.lastname: Papadopoulos
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Hagner
authors.forename: Gerhard
authors.initials: G
authors.lastname: Wagner
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D003593:Cytoplasm / Q000378:metabolism; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D014176:Protein Biosynthesis; D039381:RNA Cap-Binding Proteins / Q000378:metabolism; D012315:RNA Caps / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism*; D013499:Surface Properties; D015854:Up-Regulation
chemical_list: C112609:EIF4E2 protein, human; D039561:Eukaryotic Initiation Factor-4E; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D039381:RNA Cap-Binding Proteins; D012315:RNA Caps; D012333:RNA, Messenger; D010100:Oxygen
keywords: Breast Cancer Cells; Cancer Biology; Cap-dependent Translation; Hypoxia; Hypoxia-inducible Factor (HIF); Translation Initiation Factors; eIF4E; mRNA