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Long non-coding RNA HOTAIR promotes invasion of breast cancer cells through chondroitin sulfotransferase CHST15

Liu, Liang-Chih and Wang, Yuan-Liang and Lin, Pei-Le and Zhang, Xiang and Cheng, Wei-Chung and Liu, Shu-Hsuan and Chen, Chih-Jung and Hung, Yu and Jan, Chia-Ing and Chang, Ling-Chu and Qi, Xiaoyang and Hsieh-Wilson, Linda C. and Wang, Shao-Chun (2019) Long non-coding RNA HOTAIR promotes invasion of breast cancer cells through chondroitin sulfotransferase CHST15. International Journal of Cancer, 145 (9). pp. 2478-2487. ISSN 0020-7136. https://resolver.caltech.edu/CaltechAUTHORS:20190409-132040204

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Abstract

The long non‐coding RNA HOTAIR plays significant roles in promoting cancer metastasis. However how it conveys invasive advantage in cancer cells is not clear. Here we identify the chondroitin sulfotransferase CHST15 (GalNAc4S‐6ST) as a novel 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, 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.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1002/ijc.32319DOIArticle
ORCID:
AuthorORCID
Hsieh-Wilson, Linda C.0000-0001-5661-1714
Wang, Shao-Chun0000-0002-5477-1682
Additional Information:© 2019 Wiley. Accepted manuscript online: 09 April 2019; Manuscript accepted: 25 March 2019; Manuscript revised: 04 March 2019; Manuscript received: 27 December 2018.
Subject Keywords:HOTAIR; CHST15; long non‐coding RNA; breast cancer; invasion; chondroitin sulfate; glycosaminoglycans; RNA‐seq
Issue or Number:9
Record Number:CaltechAUTHORS:20190409-132040204
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20190409-132040204
Official Citation:Liu, L. , Wang, Y. , Lin, P. , Zhang, X. , Cheng, W. , Liu, S. , Chen, C. , Hung, Y. , Jan, C. , Chang, L. , Qi, X. , Hsieh‐Wilson, L. C. and Wang, S. (2019), Long noncoding RNA HOTAIR promotes invasion of breast cancer cells through chondroitin sulfotransferase CHST15. Int. J. Cancer, 145: 2478-2487. doi:10.1002/ijc.32319
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:94595
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:09 Apr 2019 20:31
Last Modified:03 Oct 2019 21:05

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