The role of sentrin-specific protease 2 substrate recognition in TGF-β-induced tumorigenesis

Abstract

Smad4, a common-mediator of Smads, plays a central role in forming complexes with receptor-phosphorylated Smads, and then transduces transforming growth factor (TGF)-β signals into the nuclei. Although many cellular factors are involved in TGF-β induced epithelial-to-mesenchymal transition (EMT) and cell migration, very little is known with the mechanism of Smad4 regulation on pro-oncogenes response by TGF-β. Herein, we demonstrate the interaction of Sentrin-specific protease 2 (SENP2) with Smad4 through SENP2 residue 363~400. The same segment is also important for desumoylation of Smad4, and able to relieve sumoylation-mediated TGF-β repression. The SENP2363~400 segment is critical for TGF-β-induced cell migration, which is correlated with SENP2363~400 deletion mutant failed to increase matrix metalloproteinase (MMP)-9 and EMT marker gene expression. Moreover, our results suggest that the interaction and desumoylation between SENP2 and Smad4 promote cell migration in triple-negative breast cancer cells. Altogether, our data show how SENP2 regulates its substrate for desumoylation, and also the role of SENP2 in TGF-β induced cancer cell migration.

Comprehensive in silico analysis for identification of novel candidate target genes, including DHX36, OPA1, and SENP2, located on chromosome 3q in head and neck cancers

“…Loss of SENP2 function has been demonstrated to cause suppression of matrix metalloproteinase‐9 and epithelial mesenchymal transition marker gene expressions. In addition, interaction of SENP2 and Smad4 enhanced cellular motility in triple‐negative breast cancer cells via TGF‐β induction 77 . More importantly, SENP2 was found to inhibit the SUMOylation levels of CREB‐binding protein (CBP) or murine double minute 2 (Mdm2) to promote cell cycle progression via inducing p53 degradation 74 .…”

“…In addition, interaction of SENP2 and Smad4 enhanced cellular motility in triple-negative breast cancer cells via TGF-β induction. 77 More importantly, SENP2 was found to inhibit the SUMOylation levels of CREBbinding protein (CBP) or murine double minute 2 (Mdm2) to promote cell cycle progression via inducing p53 degradation. 74 However, the function of SENP2 in carcinogenesis seems to be controversial, since many other researches demonstrated its tumor suppressive potential.…”

Unconventional protein post-translational modifications: the helmsmen in breast cancer

“…SENP2 facilitates TGF-β-Smad4 signaling pathway by desumoylating Smad4 at lys159 to promote EMT and cell migration in TNBC cells and sustain cancer stem cell properties (Fig. 5 C III) [ 149 ]. The high expression of SENP2 consequently leads to poor prognosis in TNBC patients [ 149 ].…”

“…5 C III) [ 149 ]. The high expression of SENP2 consequently leads to poor prognosis in TNBC patients [ 149 ].…”

SENP Proteases as Potential Targets for Cancer Therapy

“…SENP2 inhibited the Notch and NF-κB signaling pathways in chronic lymphocytic leukemia cells, resulting in cell apoptosis [ 49 ]. In breast cancer cells, SENP2 participated in the regulation of estrogen receptor α (ERα) signaling and transforming growth factor (TGF-β) signaling, which modulated cancer cell proliferation, migration, and invasion [ 50 , 51 ].…”