Abstract
HIF-1α has a broad impact on tumors, including enhanced utilization of glucose, tumor cell stemness, migration, metastasis and so on. In pilot study, we found that the expression of HIF-1α significantly increased in breast cancer cell lines and tissue samples with higher malignant behaviors and decreased in luminal subtype breast cancer cells and tissue samples. We analyzed and found there is one large CpG island in HIF-1α promoter around transcription start site, and the hypermethylation occurred at these CpGs and their surrounding non-CpGs sites. Epigenetic events driving tumorigenesis has been characterized. However, knowledge is lacking on the non-CpGs methylation of HIF-1α promoter in breast cancer cells. We validated that non-CpGs methylation can directly regulate HIF-1α expression by luciferase activity assay. We also found DNMT3a and Mecp2 play vital role in methylation at non-CpGs and CpGs sites. In addition, we noticed that H3K9ac modification could promote the transcription of HIF-1α in MDA-MB-231 cells by binding to the region contained hypomethylated non-CpG and CpG sites. Taken together, the hypomethylation status at non-CpG and CpG loci in HIF-1α promoter and H3K9ac modification together contribute to maintain higher HIF-1αactivity in invasive breast cancer cells when compared with the non-invasive breast cancer cells, which may establish a tissue-specific epigenetic modification pattern and point to the new directions for future understanding breast cancer therapy.
Highlights
Breast cancer is a global health problem and is one of the leading causes of cancer deaths for women[1,2]
We firstly found that only basal and HER2 positive breast cancer present higher HIF-1α expression either according to HU subtype or PAM50 subtype among six distinct groups, namely, basal, HER2 positive, luminal A, luminal B, normal-like, and non-classified breast cancer, by using GOBO online analysis (p < 0.00001, Fig. 1a upper row)
The relative HIF-1α expression levels were determined by western blotting in five human breast cancer cell lines including MCF-7, T47D, SKBR3, MDA-MB-231 and BT549, of which MCF-7 and T47D are characterized as ER-positive/ PgR-positive luminal mammary carcinoma, MDA-MB231 and BT-549 are characterized as triple-negative/ basal-B mammary carcinoma (TNBC), and SKBR3 is a cell line that overexpresses the Her[2] (Neu/ErbB-2) gene product
Summary
Breast cancer is a global health problem and is one of the leading causes of cancer deaths for women[1,2]. In China, estimates of new breast cancer cases were approximately 278,900 in 20143. Based on molecular profiling, breast malignant tumors are classified into five major subtypes: basal-. The triple negative breast cancer (TNBC) is characterized by negative expression of estrogen and progesterone receptors (ER-negative, PR-negative) as well as HER2, and accounts for approximately 16% of all breast cancer diagnoses[5,6]. TNBC is often used as a surrogate for identifying the aggressive basal breast cancer subtype, and the two patterns share many similarities, they are not biologically synonymous[7]. Hypoxia has been recognized as a common characteristic in many types of solid tumors, including TNBC. Cancer cells in a hypoxic region begin to adapt to low
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