Gain-of-function mutant p53 activates small GTPase Rac1 through SUMOylation to promote tumor progression

Abstract

Tumor suppressor p53 is frequently mutated in human cancer. Mutant p53 often promotes tumor progression through gain-of-function (GOF) mechanisms. However, the mechanisms underlying mutant p53 GOF are not well understood. In this study, we found that mutant p53 activates small GTPase Rac1 as a critical mechanism for mutant p53 GOF to promote tumor progression. Mechanistically, mutant p53 interacts with Rac1 and inhibits its interaction with SUMO-specific protease 1 (SENP1), which in turn inhibits SENP1-mediated de-SUMOylation of Rac1 to activate Rac1. Targeting Rac1 signaling by RNAi, expression of the dominant-negative Rac1 (Rac1 DN), or the specific Rac1 inhibitor NSC23766 greatly inhibits mutant p53 GOF in promoting tumor growth and metastasis. Furthermore, mutant p53 expression is associated with enhanced Rac1 activity in clinical tumor samples. These results uncover a new mechanism for Rac1 activation in tumors and, most importantly, reveal that activation of Rac1 is an unidentified and critical mechanism for mutant p53 GOF in tumorigenesis, which could be targeted for therapy in tumors containing mutant p53.

Conditional Deletion of CC2D1A Reduces Hippocampal Synaptic Plasticity and Impairs Cognitive Function through Rac1 Hyperactivation

“…At the molecular level, we showed that Cc2d1a deletion drastically downregulated SENP1 and SENP3 mRNA and protein expression and consequently repressed SENP-mediated de-SUMOylation of Rac1 to activate Rac1. This SENP-mediated de-SUMOylation of Rac1 has also been demonstrated in human cancer cells, where the de-SUMOylation activity of SENP1 is crucial for the promoting effect of mutant p53 on Rac1 activity to regulate tumor progression (Castillo-Lluva et al, 2010;Yue et al, 2017). Moreover, we observed that SUMO2/3, but not SUMO1 (data not shown), conjugation levels are increased in hippocampal CA1 tissue lysates of cKO mice.…”

“…SUMOylation is a highly dynamic process that can be reversed by SENPs (Mukhopadhyay and Dasso, 2007;Gareau and Lima, 2010;Hay, 2013). Previous studies have shown that SENP1 can interact with Rac1 and de-SUMOylate Rac1 to downregulate its activity in cells (Castillo-Lluva et al, 2010;Yue et al, 2017). We therefore examined whether Cc2d1a deletion increases basal Rac1 SUMOylation levels by decreasing expression of SENPs.…”

“…Since previous studies have reported that Rac1 can be conjugated to SUMO protein and this Rac1 SUMOylation is crucial to maintain the active Rac1-GTP form and enhance Rac1 activity (Castillo-Lluva et al, 2010;Yue et al, 2017), we therefore investigated whether Cc2d1a deletion activates Rac1 through increasing Rac1 SUMOylation levels. The Rac1 SU-MOylation levels were determined by Rac1 pull-down followed by Western blot analysis using an anti-SUMO2/3 antibody.…”

Participation of MicroRNAs in the Treatment of Cancer with Phytochemicals

“…One of the critical miRNAs involved in the progression of colorectal cancer is miR-429. It has been noticed that this miRNA is overexpressed in colorectal cancer tissues compared to their normal counterparts and that miR-429 is able to augment EMT and metastasis of colorectal cancer by modulating the expression of homeobox A5 (HOXA5) [ 89 ]. Additionally, treatments of colorectal cancer with either berberine or evodiamine result in a decrease in miR-429 expression [ 90 ], suggesting that the anti-cancer activity of both phytochemicals is partly mediated by the modulation of miR-429 levels ( Figure 1 and Table 3 ).…”

Propofol activates autophagic activity of vascular endothelial cells by inhibiting SENP1 expression and attenuates vascular endothelial injury induced by ischemia-reperfusion in orthopedic surgery

“…For example, overexpression of SENP1 inhibits the neurogenic capacity of osteosarcoma stem cells and increases their sensitivity to HSVtk/GCV [33]. In addition, p53 mutant activates GTPase RAC1 through SUMOylation pathway, and promotes the occurrence and development of tumors [34]. To further test whether SENP1 exerts its role in HUVECs, we constructed an IR model of HUVECs and carried out qRT-PCR, Western blotting, CCK-8 assay, Transwell assay and flow cytometry.…”