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Title: | SENP1 promotes hypoxia-induced cancer stemness by HIF-1α deSUMOylation and SENP1/HIF-1α positive feedback loop | Authors: | Cui, CP Wong, CCL Kai, AKL Ho, DWH Lau, YT Tsui, YM Chan, LK Cheung, TT Chok, KSH Chan, ACY Lo, RCL Lee, JMF Lee, KW Ng, IOL |
Issue Date: | 2016 | Source: | Gut, 2016, v. 66, no. 2, 313264, p. 2149-2159 | Abstract: | Objective: We investigated the effect and mechanism of hypoxic microenvironment and hypoxia-inducible factors (HIFs) on hepatocellular carcinoma (HCC) cancer stemness. Design: HCC cancer stemness was analysed by self-renewal ability, chemoresistance, expression of stemness-related genes and cancer stem cell (CSC) marker-positive cell population. Specific small ubiquitin-like modifier (SUMO) proteases 1 (SENP1) mRNA level was examined with quantitative PCR in human paired HCCs. Immunoprecipitation was used to examine the binding of proteins and chromatin immunoprecipitation assay to detect the binding of HIFs with hypoxia response element sequence. In vivo characterisation was performed in immunocompromised mice and stem cell frequency was analysed. Results: We showed that hypoxia enhanced the stemness of HCC cells and hepatocarcinogenesis through enhancing HIF-1α deSUMOylation by SENP1 and increasing stabilisation and transcriptional activity of HIF-1α. Furthermore, we demonstrated that SENP1 is a direct target of HIF-1/2α and a previously unrecognised positive feedback loop exists between SENP1 and HIF-1α. Conclusions: Taken together, our findings suggest the significance of this positive feedback loop between HIF-1α and SENP1 in contributing to the increased cancer stemness in HCC and hepatocarcinogenesis under hypoxia. Drugs that specifically target SENP1 may offer a potential novel therapeutic approach for HCC. |
Publisher: | BMJ Group | Journal: | Gut | ISSN: | 0017-5749 | EISSN: | 1468-3288 | DOI: | 10.1136/gutjnl-2016-313264 | Rights: | Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/ This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/ The following publication Cui, C. P., Wong, C. C. L., Kai, A. K. L., Ho, D. W. H., Lau, E. Y. T., Tsui, Y. M., ... & Ng, I. O. L. (2017). SENP1 promotes hypoxia-induced cancer stemness by HIF-1α deSUMOylation and SENP1/HIF-1α positive feedback loop. Gut, 66(12), 2149-2159 is available at https://doi.org/10.1136/gutjnl-2016-313264 |
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