Betulinic acid decreases Sp1 level via increasing the sumoylation of Sp1 to inhibit lung cancer growth

Abstract

Previous study has known that Sp1 inhibited by a natural product, betulinic acid (BA), involves in the cancer progression, but the mechanism still need to delineate. In this study, we found that BA treatment increases the sumoylation of Sp1 by inhibiting the SUMO1/sentrin specific peptidase 1 (SENP1), increasing the recruitment of E3 ligase, RNF4, and then results in ubiquitination and degradation in a 26S‐proteosome dependent pathway. Gene expression profile of the MMA‐treated KRAS‐induced lung cancer transgenic mice studied by the cDNA array found that 542 of genes were affected by repressing Sp1 activity. One of these important genes, cyclin A2, addressed deeply indicates that BA and MMA affect cyclin A2 expression by decreasing Sp1 stability and DNA binding affinity, respectively. Downregulation of cyclin A2 led to decrease pRb phosphorylation and cause cell cycle G2‐arrest. Finally, Sp1 level studied during in Kras‐induced lung cancer transgenic mice and clinical lung cancer specimen found that Sp1 was accumulated significantly. Taken together, this study clearly clarifies the mechanism of BA‐mediate Sp1 degradation: BA modulates the posttranslational modification, such as increased sumoylation and ubiquitination, of Sp1, to destabilize Sp1 to affect its target genes such as cyclin A2, and then repress lung cancer growth.