Carbonic anhydrase XII expression is linked to suppression of Sonic hedgehog ligand expression in triple negative breast cancer cells

Biochem Biophys Res Commun. 2019 Aug 20;516(2):408-413. doi: 10.1016/j.bbrc.2019.06.040. Epub 2019 Jun 18.


Aberrant activity of the hedgehog (Hh) pathway is prevalent in pathologies such as cancer. Improved understanding of Hh activity in the aggressive tumor cell phenotype is being pursued for development of targeted therapies. Recently, we described a link between Hh activity and carbonic anhydrase XII (CAXII) expression. Extracellular facing CAs (IX/XII) are highly expressed in hypoxia, contribute to tumor pH regulation and are thus of clinical interest. Here we have extended the investigation of potential interactions between Hh activity and CAXII utilizing genomic disruption/knockout of either GLI1 (the main transcriptional factor induced with Hh activity) or CAXII in the triple negative breast cancer cell lines MDA-MB-231 and BT-549. Knockout of GLI1 and CAXII significantly decreased hallmarks of tumor aggressiveness including proliferation and migration. Most intriguingly, CAXII knockout caused a massive induction of the Sonic hedgehog (Shh) ligand expression (gene and protein). This novel finding indicates that CAXII plays a potential role in suppression of Shh and may act in a feedback loop to regulate overall Hh activity. Enhanced knowledge of these CA-Hh interactions in future studies may be of value in understanding this currently 'incurable' subclass of breast cancer.

Keywords: CAXII; GLI1; Hedgehog (Hh) pathway; Sonic hedgehog ligand; Tumor aggressiveness.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carbonic Anhydrases / metabolism*
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Female
  • Gene Knockout Techniques
  • Genome
  • Heterozygote
  • Humans
  • Neoplasm Invasiveness
  • Triple Negative Breast Neoplasms / metabolism*
  • Zinc Finger Protein GLI1 / metabolism*


  • GLI1 protein, human
  • Zinc Finger Protein GLI1
  • Carbonic Anhydrases
  • carbonic anhydrase XII