Abstract
Abstract Objective: The reversible SUMO-posttranslational modification of protein substrates regulates various cellular processes and consistently is important for normal cell physiology. Disruption of SUMO enzymatic components supports onset of various pathophysiological disorders, including cancer. Our recent study identified a splicing event that differentially modulates expression of 2 SENP7 isoforms. The novel SENP7 variant SENP7S is the predominant SUMO protease in normal mammary epithelia; however onset of precancerous ductal carcinoma in situ (DCIS) reduces SENP7S significantly and stays low in all breast cancer (BCa) subtypes. Inversely, the full-length SENP7L isoform is upregulated in BCa and directly leads to BCa metastasis. Unlike SENP7L, SENP7S isoform contribution to carcinogenesis is unclear. Our objective is to define the biological function of this novel deSUMOylase SENP7S in normal versus cancerous epithelial cells. Results: Consistently with mRNA levels, protein levels of the 2 SENP7 isoforms are also inversely expressed in human BCa versus normal mammary epithelia. SENP7S is localized in the cytosol of MCF10-2A unlike other SUMO proteases including SENP7L that are predominantly nuclear enzymes. Beta-catenin and a component of the Beta-catenin destruction complex, Axin1 are substrates for SENP7S catalytic activity as in the absence of SENP7S, Beta-catenin and Axin 1 are both SUMOylated. Consistently, SENP7S regulates Beta-catenin signaling pathway. SUMOylated Axin1 loses its interaction with Beta-catenin, allowing the Beta-catenin to escape ubiquitylation and further proteasomal degradation. SUMOylated Beta-catenin translocates to the nucleus and activates multiple target genes that potentiate cell proliferation. Increase in cell proliferation and anchorage dependent growth of non-cancerous MCF10-2A cells was observed with inhibition of SENP7S. Additionally, SENP7S depletion potentiates anchorage independent growth of MCF10-2A with significantly greater number and size of spheroids. In comparison to the control. Loss of SENP7S also potentiates the self-renewal properties of the cells, indicative of mammary epithelial cell transformation. Conclusion: SENP7S modulates Beta-catenin stability and signaling and consequently is critical for normal mammary epithelial cell physiology. Loss of SENP7S, as observed in DCIS, initiates mammary epithelial cell transformation. Citation Format: Karami S, Lin F-M, Kumar S, Ren J, Bahnassy S, Bawa-Khalfe T. Non-nuclear SUMO dynamics regulate mammary epithelial cell transformation [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-04-08.
Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
