Long noncoding RNA HOTAIR promotes invasion of breast cancer cells through chondroitin sulfotransferase CHST15
Abstract
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.
Additional Information
© 2019 UICC. Issue Online: 01 September 2019; Version of Record online: 26 April 2019; Accepted manuscript online: 09 April 2019; Manuscript accepted: 25 March 2019; Manuscript revised: 04 March 2019; Manuscript received: 27 December 2018. Funding Information: National Health Research Institute. Grant Number: NHRI‐EX106‐10602BI. National Institute of General Medical Sciences. Grant Number: R01 GM093627. Ministry of Science and Technology. Grant Number: MOST‐106‐2320‐B‐039‐046. Ministry of Health and Welfare. Grant Number: MOHW107‐TDU‐B‐212‐112015. Drug Development Center of the China Medical University. China Medical University Hospital. Grant Number: DMR‐CELL‐17025. China Medical University Research Center for New Drug Development.Attached Files
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Additional details
- Eprint ID
- 98776
- Resolver ID
- CaltechAUTHORS:20190920-104021676
- NHRI‐EX106‐10602BI
- National Health Research Institute
- R01 GM093627
- NIH
- MOST‐106‐2320‐B‐039‐046
- Ministry of Science and Technology (Taipei)
- MOHW107‐TDU‐B‐212‐112015
- Ministry of Health and Welfare (Taipei)
- DMR‐CELL‐17025
- China Medical University
- Created
-
2019-09-20Created from EPrint's datestamp field
- Updated
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2021-11-16Created from EPrint's last_modified field