2. Academic Validation
  3. Inhibiting Importin 4-mediated nuclear import of CEBPD enhances chemosensitivity by repression of PRKDC-driven DNA damage repair in cervical cancer

Inhibiting Importin 4-mediated nuclear import of CEBPD enhances chemosensitivity by repression of PRKDC-driven DNA damage repair in cervical cancer

  • Oncogene. 2020 Aug;39(34):5633-5648. doi: 10.1038/s41388-020-1384-3.
Yang Zhou  # 1 2,  Fei Liu  # 1 3,  Qinyang Xu 1,  Bikang Yang 1,  Xiao Li 1,  Shuheng Jiang 4,  Lipeng Hu 4,  Xueli Zhang 4,  Lili Zhu 4,  Qing Li 4,  Xiaolu Zhu 1,  Hongfang Shao 5,  Miao Dai 6,  Yifei Shen 7,  Bo Ni 8,  Shuai Wang 9,  Zhigang Zhang 10,  Yincheng Teng 11 12
Affiliations

Affiliations

  • 1 Department of Gynecology and Obstetrics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai, 200233, PR China.
  • 2 Department of Gynecology and Obstetrics, Shanghai Eighth People's Hospital, Affiliated to Jiangsu University, Shanghai, 200233, PR China.
  • 3 Global Clinical Medical Affairs (GCMA), Shanghai Henlius Biotech, Inc. 7/F, Innov Tower, Zone A, No.1801 HongMei Rd. Xuhui District, Shanghai, 200233, PR China.
  • 4 State Key Laboratory for Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai Jiao Tong University, Shanghai, PR China.
  • 5 Center of Reproductive Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai, 200233, PR China.
  • 6 Department of Gynecologic Oncology, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, PR China.
  • 7 Department of Orthopedics, Shanghai East Hospital, School of Medicine, Shanghai Tongji University, Shanghai, 200120, PR China.
  • 8 Department of Gastrointestinal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200217, PR China.
  • 9 Jacobi medical center, bronx, New York, NY, 10461, USA.
  • 10 State Key Laboratory for Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai Jiao Tong University, Shanghai, PR China. zzhang@shsci.org.
  • 11 Department of Gynecology and Obstetrics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai, 200233, PR China. ycteng@sjtu.edu.cn.
  • 12 Department of Gynecology and Obstetrics, Shanghai Eighth People's Hospital, Affiliated to Jiangsu University, Shanghai, 200233, PR China. ycteng@sjtu.edu.cn.
  • # Contributed equally.
PMID: 32661323 DOI: 10.1038/s41388-020-1384-3
Abstract

Cervical Cancer (CC) remains highest in the mortality of female reproductive system cancers, while cisplatin (CDDP) resistance is the one of main reasons for the lethality. Preceding evidence has supported that karyopherins are associated with chemoresistance. In this study, we simultaneously compared CDDP-incomplete responders with CDDP-complete responders of CC patients and CDDP-insensitive CC cell lines with CDDP-sensitive group. We finally identified that DNA-PKcs (PRKDC) was related to CDDP sensitivity after overlapping in CC sample tissues and CC cell lines. Further functional assay revealed that targeting PRKDC by shRNA and NU7026 (specific PRKDC inhibitor) could enhance CDDP sensitivity in vitro and in vivo, which was mediated by impairing DNA damage repair pathway in CC. Mechanistically, we found that PRKDC was transcriptionally upregulated by CCAAT/enhancer-binding protein delta (CEBPD), while intriguingly, CDDP treatment strengthened the transcriptional activity of CEBPD to PRKDC. We further disclosed that Importin 4 (IPO4) augmented the nuclear translocation of CEBPD through nuclear localization signals (NLS) to activate PRKDC-mediated DNA damage repair in response to CDDP. Moreover, we demonstrated that IPO4 and CEBPD knockdown improved CDDP-induced cytotoxicity in vitro and in vivo. Together, we shed the novel insight into the role of IPO4 in chemosensitivity and provide a clinical translational potential to enhance CC chemosensitivity since the IPO4-CEBPD-PRKDC axis is actionable via NU7026 (PRKDC inhibitor) or targeting IPO4 in combination with CDDP.

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