J Biol Chem. 2013 Jun 28;288(26):18732-42.

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.

Yi T, Papadopoulos E, Hagner PR, Wagner G.

Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA.

 

Abstract

Hypoxia promotes tumor evolution and metastasis and hypoxia induced 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 promotes cap-dependent translation of selective mRNAs through upregulation of eIF4E1 in hypoxic breast cancer cells. Hypoxia promoted breast cancer tumorsphere growth is HIF-1α dependent. We find that eIF4E1, not eIF4E2 or eIF4E3, is the dominant eIF4E-family member in breast cancer cells under both normoxia and hypoxia conditions. eIF4E3 expression is largely sequestered in breast cancer cells at normoxia and hypoxia. Hypoxia upregulates the expression of eIF4E1 and eIF4E2, while only eIF4E1 expression is HIF-1α dependent. In hypoxic cancer cells, HIF-1α upregulated eIF4E1 enhances cap-dependent translation of a subset of mRNAs encoding proteins important for breast cancer cell mammosphere growth. Searching for correlations we discovered that human eIF4E1 promoter harbors multiple potential hypoxia response elements (HREs). Furthermore, using chromatin immunoprecipitation (CHIP), luciferase and point mutation assays, we found that HIF-1α utilizes HREs 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 upregulating 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.

KEYWORDS: Breast Cancer Cells, Cancer Biology, Cap-dependent Translation, Hypoxia, Hypoxia-inducible Factor (HIF), Translation Initiation Factors, eIF4E, mRNA

PMID: 23667251

 

Supplementary

The study by Yi et al. focused on the molecular mechanisms of translation in cancer under low oxygen conditions (hypoxia). Hypoxia promotes cancer growth, tumor angiogenesis, cancer stem cell self-renewal and dissemination. Cancer cells at hypoxia undergo genetic and adaptive changes in regulation of translation that facilitate production of proteins involved in cancer cell survival and proliferation. Translation is generally suppressed at hypoxia contributing to conserve energy and to sustain survival during the period of inefficient ATP production. On the other hand, a subset of mRNAs involved in the adaptive responses to hypoxia are preferentially translated in cancer cells. The translation mechanisms underlying the adaptive and malignant phenotype of tumors and experience hypoxia have remained obscure.

Yi et al. provided evidence that hypoxia induced factor -1α (HIF-1α) promotes cap-dependent translation of a subset of mRNAs through transcriptionally upregulating translation initiation factor eIF4E1 in hypoxic cancer cells. Firstly, the authors identified that hypoxia promoted breast cancer cell tumorsphere growth is HIF-1α dependent. The elevated cellular eIF4E1 depends on the increased HIF-1α levels in cancer cells at hypoxia. Secondly, a number of select mRNAs were found to be translationally upreguleted via elevated eIF4E1 in hypoxia and required cap-dependent initiation format These includ cyclin-1, c-Myc, eIF4G1, VEGF-A165, but not eIF1A, or eIF5, or GAPDH. The breast cancer cells at hypoxia studied here are preferentially sensitive to the 4EGI-1, a small molecule inhibitor of eIF4E1. Thirdly, the authors elucidated the underlying molecular mechanisms that HIF-1α specifically utilizes the hypoxia response elements (HREs) in the eIF4E1 proximal promoter region to up-regulate eIF4E1 expression. Point mutations in these HREs of eIF4E1 promoter neutralize the promotion effects of HIF-1α on eIF4E1. These findings extend the understanding of adaptive advantages for the protein synthesis mechanisms in cancer cells at hypoxia.

Gerhard Wagner-fig1

Schematic diagram for HIF-1α functions in cap-dependent translation of selective mRNAs, cell proliferation and tumorsphere growth of cancer cells in low O2 environment.

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