Collagen prolyl 4-hydroxylase (P4H) expression and collagen hydroxylation in cancer cells are necessary for breast cancer progression. Here, we show that P4H alpha 1 subunit (P4HA1) protein expression is induced in triple-negative breast cancer (TNBC) and HER2 positive breast cancer. By modulating alpha ketoglutarate (α-KG) and succinate levels P4HA1 expression reduces proline hydroxylation on hypoxia-inducible factor (HIF) 1α, enhancing its stability in cancer cells. Activation of the P4HA/HIF-1 axis enhances cancer cell stemness, accompanied by decreased oxidative phosphorylation and reactive oxygen species (ROS) levels. Inhibition of P4HA1 sensitizes TNBC to the chemotherapeutic agent docetaxel and doxorubicin in xenografts and patient-derived models. We also show that increased P4HA1 expression correlates with short relapse-free survival in TNBC patients who received chemotherapy. These results suggest that P4HA1 promotes chemoresistance by modulating HIF-1-dependent cancer cell stemness. Targeting collagen P4H is a promising strategy to inhibit tumor progression and sensitize TNBC to chemotherapeutic agents.
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We acknowledge the assistance of the following Markey Cancer Center Shared Resource Facilities, all of which are supported by the grant P30 CA177558: the Biospecimen and Tissue Procurement Shared Resource Facility for assistance in tissue fixation and section; the Flow Cytometry and Cell Sorting Core Facility for performing FACS analysis; and the Redox Metabolism Shared Resource Facility for performing Seahorse experiments. This study was supported by start-up funding from Markey Cancer Center and funding support from NCI (1R01CA207772, 1R01CA215095, and 1R21CA209045 to R.X.), Markey Cancer Center CCSG pilot funding (P30 CA177558), and United States Department of Defense (W81XWH-15-1-0052 to R.X.).
Supplementary Information accompanies this paper at https://doi.org/10.1038/s41467-018-06893-9.
Xiong, Gaofeng; Stewart, Rachel L.; Chen, Jie; Gao, Tianyan; Scott, Timothy L.; Samayoa, Luis M.; O'Connor, Kathleen L.; Lane, Andrew N.; and Xu, Ren, "Collagen Prolyl 4-Hydroxylase 1 is Essential for HIF-1α Stabilization and TNBC Chemoresistance" (2018). Markey Cancer Center Faculty Publications. 127.