HP1Γ sensitizes cervical cancer cells to cisplatin through the suppression of UBE2L3

Sang Ah Yi, Go Woon Kim, Jung Yoo, Jeung Whan Han, So Hee Kwon

Research output: Contribution to journalArticlepeer-review

Abstract

Cisplatin is the most frequently used agent for chemotherapy against cervical cancer. However, recurrent use of cisplatin induces resistance, representing a major hurdle in the treatment of cervical cancer. Our previous study revealed that HP1γ suppresses UBE2L3, an E2 ubiquitin conjugating enzyme, thereby enhancing the stability of tumor suppressor p53 specifically in cervical cancer cells. As a follow-up study of our previous findings, here we have identified that the pharmacological substances, leptomycin B and doxorubicin, can improve the sensitivity of cervical cancer cells to cisplatin inducing HP1γ-mediated elevation of p53. Leptomycin B, which inhibits the nuclear export of HP1γ, increased cisplatin-dependent apoptosis induction by promoting the activation of p53 signaling. We also found that doxorubicin, which induces the DNA damage response, promotes HP1γ-mediated silencing of UBE2L3 and increases p53 stability. These effects resulted from the nuclear translocation and binding of HP1γ on the UBE2L3 promoter. Doxorubicin sensitized the cisplatin-resistant cervical cancer cells, enhancing their p53 levels and rate of apoptosis when administered together with cisplatin. Our findings reveal a therapeutic strategy to target a specific molecular pathway that contributes to p53 degradation for the treatment of patients with cervical cancer, particularly with cisplatin resistance.

Original languageEnglish
Article number5976
Pages (from-to)1-15
Number of pages15
JournalInternational journal of molecular sciences
Volume21
Issue number17
DOIs
Publication statusPublished - 2020 Sep 1

Bibliographical note

Funding Information:
Funding: This research was funded by National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (2017R1A6A3A04001986 to S.A.Y., 2017R1A2B3002186 and 2019R1A5A2027340 to J.-W.H., 2018R1A6A1A03023718 and 2019R1A2C1008619 to S.H.K.).

All Science Journal Classification (ASJC) codes

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

Fingerprint Dive into the research topics of 'HP1Γ sensitizes cervical cancer cells to cisplatin through the suppression of UBE2L3'. Together they form a unique fingerprint.

Cite this