Collagen prolyl 4-hydroxylase 1 is essential for HIF-1α stabilization and TNBC chemoresistance

Nat Commun. 2018 Oct 26;9(1):4456. doi: 10.1038/s41467-018-06893-9.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cell Line
  • Collagen / metabolism
  • Drug Resistance, Neoplasm*
  • Female
  • Gene Expression
  • Gene Knockdown Techniques
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Ketoglutaric Acids / metabolism
  • Mice
  • Mice, SCID
  • Neoplasm Metastasis / prevention & control
  • Neoplasm Recurrence, Local / metabolism
  • Neoplasm Recurrence, Local / prevention & control
  • Neoplastic Stem Cells / enzymology
  • Neoplastic Stem Cells / metabolism
  • Procollagen-Proline Dioxygenase / antagonists & inhibitors
  • Procollagen-Proline Dioxygenase / genetics*
  • Procollagen-Proline Dioxygenase / metabolism*
  • RNA, Messenger / metabolism
  • Reactive Oxygen Species / metabolism
  • Survival Analysis
  • Triple Negative Breast Neoplasms / enzymology*
  • Triple Negative Breast Neoplasms / metabolism
  • Triple Negative Breast Neoplasms / pathology
  • Triple Negative Breast Neoplasms / physiopathology*


  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Ketoglutaric Acids
  • RNA, Messenger
  • Reactive Oxygen Species
  • Collagen
  • P4HA1 protein, human
  • Procollagen-Proline Dioxygenase