This study is led by Dr. Donglai Wang (Institute of Basic Medical Sciences & School of Basic Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College) and Dr. Wei-Guo Zhu (Shenzhen University Health Science Center). The experiments are primarily carried out by Han Yao and Wenbin Xu (Institute of Basic Medical Sciences & School of Basic Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College). This study revealed a previously unknown p53-SET-PP2A feedback loop that can be utilized for cancer therapy. The researchers designed a combined therapeutic strategy by simultaneously administrating p53 activator and SET antagonist, and observed a dramatic synergistic effect on tumor suppression (see below Figure 1).
Previous work conducted by Dr. Donglai Wang and his colleagues in 2016 indicated that the oncoprotein SET interacted with the tumor suppressor p53 and negatively regulated p53 transactivity by serving as a co-repressor of p53. In current study, the researchers further identified p53 as a key regulator that transcriptionally repressed the expression of SET, by which SET-mediated repression of p53 was then alleviated. Since SET also acts as an endogenous inhibitor of the tumor suppressor PP2A by interacting PP2Ac (PP2A catalytic subunit), p53-induced SET repression also potently revived PP2A phosphatase activity. Moreover, targeting SET-PP2Ac interaction by the FDA-approval compound FTY720 enhanced stress-induced p53 activation via PP2A-mediated dephosphorylation of p53 on threonine 55 (Thr55). These molecular events reveal a p53-SET-PP2A feedback loop in cells.
To potentiate p53-SET-PP2A feedback loop in cancer therapy, the researchers developed a combination therapy strategy by using p53 activator (e.g., Nutlin) and SET antagonist (e.g., FTY720) for cancer treatment. The researchers found that individual treatment was prone to induce cell growth inhibition rather than cell death. However, the combination therapy resulted in marked cell death, which was considered as a more direct manner to eliminate cancer cells. Therefore, this combined therapeutic strategy exhibited obvious synergistic effects on tumor suppression.
This study reveals a mechanistic insight into the regulation of oncoprotein SET that coordinates the functional modulation of two key tumor suppressive pathways including p53 and PP2A, and raises a potential strategy for cancer therapy by stimulating p53-SET-PP2A feedback loop.
See the article:
The repression of oncoprotein SET by the tumor suppressor p53 reveals a p53-SET-PP2A feedback loop for cancer therapy
Science China Life Sciences