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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.

SUBMITTER: Liu LC

PROVIDER: S-EPMC7263025 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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

Liu Liang-Chih LC Wang Yuan-Liang YL Lin Pei-Le PL Zhang Xiang X Cheng Wei-Chung WC Liu Shu-Hsuan SH Chen Chih-Jung CJ Hung Yu Y Jan Chia-Ing CI Chang Ling-Chu LC Qi Xiaoyang X Hsieh-Wilson Linda C LC Wang Shao-Chun SC

International journal of cancer 20190426 9

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- ...[more]

PMID: 30963568

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Project description:ObjectivesAccumulating evidence demonstrated that the long noncoding RNA (lncRNA) HOTAIR (Hox transcript antisense intergenic RNA) plays key role in renal cell carcinoma (RCC) malignancy, while microRNA-124 (miR-124) is a tumour suppressor in RCC. The aim of this work was to assess the biological function of HOTAIR and to explore underlying mechanism involved in HOTAIR/miR-124/alpha-2, 8-sialyltransferase 4 (ST8SIA4) axis-regulated progression in RCC.Materials and methodsReal-time PCR analyses and western blots were performed to the levels of HOTAIR, miR-124 and ST8SIA4 expression in human RCC tissues and RCC cell lines (ACHN and 786-O). Bioinformatics analysis and dual-luciferase reporter assay were used to illustrate relationship between HOTAIR and miR-124 in RCC. Colony formation assays, EdU assays, Ki67 assays and apoptosis assays were taken to evaluate cell proliferation. Tumour xenograft was created to explore the functions of HOTAIR and ST8SIA4 in tumorigenesis in vivo. Migration assays, invasion assays and cell adhesion assays and were also taken to analyse the carcinoma progression.ResultsIn this study, HOTAIR level was confirmed to be significantly upregulated in RCC samples and RCC cell lines compared with those in the paired adjacent tissues and normal renal cell line. Overexpression of HOTAIR promoted the capability of proliferation, migration and invasion in RCC cell lines. HOTAIR directly bound to miR-124, while miR-124 mediated the expression of ST8SIA4 in RCC cell lines. ST8SIA4 was upregulated in RCC tissues and RCC cell lines. Ectopic expression of ST8SIA4 modulated the proliferation, migration and invasion of RCC cells. Further results indicated that HOTAIR promoted the proliferation and metastasis as a competing endogenous RNA to regulate ST8SIA4 expression by sponging miR-124 in RCC.ConclusionsOur results demonstrated that HOTAIR mediated RCC progression in part through miR-124/ST8SIA4 axis, which functioned as a new prognostic biomarker in RCC.

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

Publications

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

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