Novel SUMO-Protease SENP7S Regulates β-catenin Signaling and Mammary Epithelial Cell Transformation

Abstract

SUMO post-translational modification of proteins or SUMOylation ensures normal cell function. Disruption of SUMO dynamics prompts various pathophysiological conditions, including cancer. The burden of deSUMOylating the large SUMO-proteome rests on 6 full-length mammalian SUMO-proteases or SENP. While multiple SENP isoforms exist, the function of these isoforms remains undefined. We now delineate the biological role of a novel SENP7 isoform SENP7S in mammary epithelial cells. SENP7S is the predominant SENP transcript in human mammary epithelia but is significantly reduced in precancerous ductal carcinoma in situ and all breast cancer subtypes. Like other SENP family members, SENP7S has SUMO isopeptidase activity but unlike full-length SENP7L, SENP7S is localized in the cytosol. In vivo, SUMOylated β-catenin and Axin1 are both SENP7S-substrates. With knockdown of SENP7S in mammary epithelial cells, Axin1-β-catenin interaction is lost and β-catenin escapes ubiquitylation-dependent proteasomal degradation. SUMOylated β-catenin accumulates at the chromatin and activates multiple oncogenes. Hence, non-tumorigenic MCF10-2A cells with reduced SENP7S exhibit greater cell proliferation and anchorage-dependent growth. SENP7S depletion directly potentiates tumorigenic properties of MCF10-2A cells with induction of anchorage-independent growth and self-renewal in 3D-spheroid conditions. Collectively, the results identify SENP7S as a novel mediator of β-catenin signaling and normal mammary epithelial cell physiology.

Hormonal and spatial control of SUMOylation in the human and mouse adrenal cortex

“…Finally, the decreasing gradient of SUMOylation in the adrenal cortex also suggests its possible involvement in the establishment and/or maintenance of cortical zonation. Increased SUMOylation consecutive to depletion of SENP1/2/7 proteins was reported in various models to activate the WNT/b-catenin pathway by increasing b-catenin stability (62,63) and by promoting its nuclear translocation (64,65). The ability of SUMOylation to activate the WNT pathway is likely to explain the intense staining observed in zG.…”

Association of SENPs single-nucleotide polymorphism and breast cancer in Chinese population

“…Nevertheless, SENP7L protein is elevated in invasive carcinoma. [28] Previously, it was showed that SENP7 is required for chromatin relaxation in response to DNA damage, for homologous recombination repair and for cellular resistance to DNA-damaging agents. [29] It was also demonstrated that targeted knockdown of the SENP7 gene transcript NM_001077203.2 alters Wnt-activated β-catenin signaling in a sarcoma cell line.…”

SUMOylation Wrestles With the Occurrence and Development of Breast Cancer

“…Another study revealed that deletion of SENP7S can directly enhance the tumorigenicity of MCF-10-2A cells. Mechanistically, SENP7 loss enhances the SUMOylation of β-catenin, and SUMOylated β-catenin is transported to the nucleus and promotes the transcription of oncogenes, including c-Myc, cyclin D, and Aurora kinase, ultimately promoting metastasis and invasion of breast cancer ( 38 ).…”