Alginate Oligosaccharide Attenuates α2,6--Sialylation Modification to Inhibit Prostate Cancer Cells Growth via Hippo / YAP Pathway

Abstract

Background: Alginate oligosaccharide (AOS), a water-soluble marine plant oligosaccharide, was obtained by enzymatic hydrolysis of sodium alginate. Many studies have shown chitosan oligosaccharides can inhibit various tumors. Although AOS has been shown to induce apoptosis in osteosarcoma with fewer side effects, the inhibitory effect of AOS on prostate cancer and its molecular mechanism remain obscure. Methods: Luciferase reporter assay was used to detect effect of AOS on transcriptional activity of ST6Gal-1 promoter and identification of core functional regions; Chromatin immunoprecipitation (CHIP) was used to further validate the transcription factor interacting with the core region of ST6Gal-1 promoter; Co-immunoprecipitation (Co-IP) was used to verify the protein interaction between transcription factor c-Jun that was interacted with ST6Gal-1 promoter and YAP. The change of tumor-forming ability after AOS treatment was detected in athymic nude mice in vivo. Statistical significance was estimated by a two-tailed Student’s t-test and ANOVA. Findings: This study showed AOS inhibited cell growth, which was consistent with attenuation of α2,6-sialylation modification. Meanwhile, AOS inhibited activity of ST6Gal-1 promoter and affected transcriptional process. In addition, AOS could activate Hippo/YAP pathway and block the recruitment of coactivator YAP and c-Jun to ST6Gal-1 promoter. Furthermore, YAP interacted with transcription factor c-Jun to regulate transcriptional activity of downstream target ST6Gal-1 gene. Consistent with the in vitro data, AOS suppressed tumorigenicity of prostate cancer cells via Hippo/YAP pathway in vivo. Interpretation: AOS results in slowing proliferation of prostate cancer and can be developed as an anti-tumor adjuvant for treatment of prostate cancer cells. Funding Statement: This work was supported by the National Natural Science Foundation of China (31470799); Natural Science Foundation of Liaoning Province (20170540288); Special Fund of Dalian city for Distinguished Young Scholars (2017RJ07) and National Key R＆D Program of China (2017YF0200900). Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: Animal care and experimental procedures were performed in accordance with a protocol approved by the Institutional Animal Care and Ethics Committee of Dalian Medical University (AEE18033). In addition, all experiments in the present study were consistent with the National Institutes of Health guide for the care and use of Laboratory animals.