P4HA1 is a new regulator of the HIF-1 pathway in breast cancer

Abstract

Hypoxia-Inducible Factor (HIF)-1 is a transcription factor that plays the key role in response to low oxygen concentrations, or hypoxia. Activation of the HIF-1 pathway is not only crucial for normal tissue development and function, but also involved in disease progression, such as cancer. Cancer cells proliferate rapidly in solid tumors, and thus, solid tumors consume much more oxygen and nutrients than normal tissue and generate oxygen tension. It is well established that oxygen tension in solid tumor tissue induces the aberrant activation of the HIF-1 pathway, and subsequently promotes angiogenesis and tumor progression. Breast cancer is a heterogeneous disease and can be classified into luminal, Her2 positive, and triple negative (TNBC) subtypes base on ER/PR and Her2 expression in the breast cancer tissue. HIF-1 activation is observed in all breast cancer subtypes; interestingly, the HIF-1 pathway is hyperactivated in TNBCs compared to other subtypes. The differential activation of the HIF-1 pathway in breast cancer subtypes suggests that oxygen-independent pathways may be involved in HIF-1 regulation during TNBC progression. However, these pathways have not been well-characterized. We demonstrate that collagen proly 4 hydroxylase 1 (P4H1) induces HIF-1α expression at the protein level by modulating α-ketoglutarate (α-KG) and succinate levels. These results reveal a novel link between collagen hydroxylation and activation of the HIF-1 pathway and unveil a new HIF-1 regulation mechanism in TNBC.