Antagonizing CDK8 Sensitizes Colorectal Cancer to Radiation Through Potentiating the Transcription of e2f1 Target Gene apaf1

Bin Chen; Pengbo Wen; Guanshuo Hu; Yang Gao; Xiaojing Qi; Kaili Zhu; Shaopeng Chen; Lijun Wu; An Xu; Guoping Zhao

doi:10.3389/fcell.2020.00408

Antagonizing CDK8 Sensitizes Colorectal Cancer to Radiation Through Potentiating the Transcription of e2f1 Target Gene apaf1

Front Cell Dev Biol. 2020 Jun 12:8:408. doi: 10.3389/fcell.2020.00408. eCollection 2020.

Authors

Bin Chen^{1

2}, Pengbo Wen^{1

2}, Guanshuo Hu^{1

2}, Yang Gao^{1

2}, Xiaojing Qi^{1

2}, Kaili Zhu^{1

2}, Shaopeng Chen¹, Lijun Wu¹, An Xu¹, Guoping Zhao¹

Affiliations

¹ Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Anhui Province Key Laboratory of Environmental Toxicology and Pollution Control Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, China.
² University of Science and Technology of China, Hefei, China.

Abstract

Radiotherapy is an essential curative treatment modality for colorectal cancer. Apoptosis is the major mechanism of IR-induced cell death and aberrant apoptotic signaling results in radioresistance, which is a hallmark of most, perhaps all, types of human cancers. Potentiating the induction of apoptosis is an emerging strategy for cancer radiotherapy. Here, we determined that targeting CDK8 selectively radiosensitized colorectal cancer through the mitochondria-dependent intrinsic apoptotic signaling, which was mediated through the induction of the transcription of apaf1 that was e2f1- and not p53-dependent. Importantly, the enhanced transcriptional activity of e2f1 was dependent on the kinase activity of CDK8 itself and not on the assembling of the mediator complex. In addition, clinical inhibitor, and in vivo studies confirmed the radiosensitizing effect of CDK8. Our results provide a new targeting strategy to improve the radiotherapy of CRC.

Keywords: CDK8; apaf1; apoptosis; e2f1; radiotherapy; transcriptional regulation.