Long noncoding RNA HOTAIR promotes invasion of breast cancer cells through chondroitin sulfotransferase CHST15

Int J Cancer. 2019 Nov 1;145(9):2478-2487. doi: 10.1002/ijc.32319. Epub 2019 Apr 26.


The long noncoding RNA HOTAIR plays significant roles in promoting cancer metastasis. However, how it conveys an invasive advantage in cancer cells is not clear. Here we identify the chondroitin sulfotransferase CHST15 (GalNAc4S-6ST) as a novel HOX transcript antisense intergenic RNA (HOTAIR) target gene using RNA profiling and show that CHST15 is required for HOTAIR-mediated invasiveness in breast cancer cells. CHST15 catalyzes sulfation of the C6 hydroxyl group of the N-acetyl galactosamine 4-sulfate moiety in chondroitin sulfate to form the 4,6-disulfated chondroitin sulfate variant known as the CS-E isoform. We show that HOTAIR is necessary and sufficient for CHST15 transcript expression. Inhibition of CHST15 by RNA interference abolished cell invasion promoted by HOTAIR but not on HOTAIR-mediated migratory activity. Conversely, reconstitution of CHST15 expression rescued the invasive activity of HOTAIR-depleted cells. In corroboration with this mechanism, blocking cell surface chondroitin sulfate using a pan-CS antibody or an antibody specifically recognizes the CS-E isoform significantly suppressed HOTAIR-induced invasion. Inhibition of CHST15 compromised tumorigenesis and metastasis in orthotopic breast cancer xenograft models. Furthermore, the expression of HOTAIR closely correlated with the level of CHST15 protein in primary as well as metastatic tumor lesions. Our results demonstrate a novel mechanism underlying the function of HOTAIR in tumor progression through programming the context of cell surface glycosaminoglycans. Our results further establish that the invasive and migratory activities downstream of HOTAIR are distinctly regulated, whereby CHST15 preferentially controls the arm of invasiveness. Thus, the HOTAIR-CHST15 axis may provide a new avenue toward novel therapeutic strategies and prognosis biomarkers for advanced breast cancer.

Keywords: CHST15; HOTAIR; RNA-seq; breast cancer; chondroitin sulfate; glycosaminoglycans; invasion; long noncoding RNA.

Publication types

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

MeSH terms

  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology*
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Cell Proliferation / genetics
  • Disease Progression
  • Female
  • Gene Expression Regulation, Neoplastic / genetics
  • Humans
  • Membrane Glycoproteins / genetics*
  • Neoplasm Invasiveness / genetics*
  • Neoplasm Invasiveness / pathology
  • RNA Interference
  • RNA, Long Noncoding / genetics*
  • RNA, Small Interfering / genetics
  • Sulfotransferases / genetics*


  • CHST15 protein, human
  • HOTAIR long untranslated RNA, human
  • Membrane Glycoproteins
  • RNA, Long Noncoding
  • RNA, Small Interfering
  • Sulfotransferases
  • chondroitin 4-sulfotransferase