Hypoxia induces PTHrP gene transcription in human cancer cells through the HIF-2α.
Parathyroid hormone-related protein (PTHrP) expressed by human cancer cells enhances tumor cell growth and metastasis in vivo and it is considered as the major factor responsible for humoral hypercalcemia of malignancy. Hypoxia is a widespread feature of most solid tumors. Here, we studied the effects of hypoxia on PTHrP expression. We found that PTHrP is transcriptionally induced by prolonged (48 h) hypoxia in multiple human cancer and endothelial cell lines. Pharmacological up or downregulation of hypoxia-inducible factor (HIF) resulted in induction or reduction of PTHrP levels, respectively, implying that PTHrP hypoxic induction is mediated by HIF pathway. Analysis of PTHrP promoter revealed that both HIF-1α and HIF-2α subunits bind to specific hypoxia-responsive elements (HRE) within the P2 promoter of PTHrP. However, only HIF-2α can drive direct transcriptional activation, which can be abolished by mutation in the specific HRE. To the best of our knowledge, these results provide for the first time evidence that PTHrP is regulated by hypoxia in cancer and endothelial cells through the HIF-2 pathway. We suggest that HIF-2 induced by intratumoral hypoxia or by other genetic alterations may contribute to the pathogenesis of hypercalcemia of malignancy and cancer aggressiveness by stimulation of PTHrP expression.
Manisterski
Michal
M
Department of Pediatrics, Dana Children's Hospital, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv, Israel.
Golan
Maya
M
Amir
Sharon
S
Weisman
Yosef
Y
Mabjeesh
Nicola J
NJ
D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D044162:Parathyroid Hormone-Related Protein / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000378:metabolism; D015533:Transcriptional Activation; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D044162:Parathyroid Hormone-Related Protein; D000099162:Endothelial PAS Domain-Containing Protein 1