HIF-O-Glcnac Axis - Implications for Breast Cancer Metastasis

Abstract

Background/aims: Hypoxia-inducible factor isoforms HIF1 and HIF2 are crucial in the hypoxia response but might also support cancer progression, including breast cancer. O-GlcNAcylation, a post-translational modification regulated by the OGT enzyme, is also emerging as a contributor to breast cancer malignancy. This study aimed to elucidate the role of HIF1 and HIF2 in breast cancer progression and their relationship to O-GlcNAcylation.

Methods: We analyzed clinical breast cancer samples, assessing HIF1, HIF2, OGT, and the total O-GlcNAcylation levels by the Western Blot method and their association with clinicopathological characteristics. Additionally, we employed in vitro silencing of OGT, HIF1, and HIF2 in breast cancer cell lines (MCF-7 and MDA-MB-231) to examine their effects on genes expression and cell migration (wound healing assay). A p-value < 0.05 was considered to indicate a statistically significant difference.

Results: In breast cancer samples, both HIF isoform levels were elevated in tumors, but HIF2 was associated with lymph node metastasis. A negative correlation was found between HIF2 and O-GlcNAcylation. Silencing HIF2 slowed cell migration, increased O-GlcNAcylation, and decreased the expression of metastasis-related genes. Silencing HIF1 or OGT resulted in the increased expression of these genes, potentially due to increased levels of HIF2.

Conclusion: Our findings suggest that the HIF-O-GlcNAc axis plays a critical role in breast cancer progression and metastasis, with HIF1 and HIF2 exhibiting distinct functions.

Keywords: Hypoxia-inducible factor ; O-GlcNAcylation ; OGT ; Breast cancer ; Metastasis.