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HPV-mediated nuclear export of HP1γ drives cervical tumorigenesis by downregulation of p53

Authors
 Sang Ah Yi  ;  Dong Hoon Lee  ;  Go Woon Kim  ;  Hyun-Wook Ryu  ;  Jong Woo Park  ;  Jaecheol Lee  ;  Jihoon Han  ;  Jee Hun Park  ;  Hwamok Oh  ;  Jieun Lee  ;  Junjeong Choi  ;  Hyun-Soo Kim  ;  Hyeok Gu Kang  ;  Da-Hyun Kim  ;  Kyung-Hee Chun  ;  Jueng Soo You  ;  Jeung-Whan Han  ;  So Hee Kwon 
Citation
 CELL DEATH AND DIFFERENTIATION, Vol.27(9) : 2537-2551, 2020-09 
Journal Title
 CELL DEATH AND DIFFERENTIATION 
ISSN
 1350-9047 
Issue Date
2020-09
Abstract
E6 oncoprotein derived from high-risk human papillomavirus (HPV) drives the development of cervical cancer through p53 degradation. Because cervical cancer therapies to inactivate HPV or E6 protein are not available, alternative strategies are required. Here, we show that HPV-mediated nuclear export of human heterochromatin protein 1γ (HP1γ) reduces the stability of p53 through UBE2L3-mediated p53 polyubiquitination during cervical cancer progression. In general, HP1 plays a key role in heterochromatin formation and transcription in the nucleus. However, our immunostaining data showed that the majority of HP1γ is localized in the cytoplasm in HPV-mediated cervical cancer. We found that HPV E6 protein drives unusual nuclear export of HP1γ through the interaction between the NES sequence of HP1γ and exportin-1. The mutation of the NES sequence in HP1γ led to nuclear retention of HP1γ and reduced cervical cancer cell growth and tumor generation. We further discovered that HP1γ directly suppresses the expression of UBE2L3 which drives E6-mediated proteasomal degradation of p53 in cervical cancer. Downregulation of UBE2L3 by overexpression of HP1γ suppressed UBE2L3-dependent p53 degradation-promoting apoptosis of cervical cancer cells. Our findings propose a useful strategy to overcome p53 degradation in cervical cancer through the blockage of nuclear export of HP1γ.
Files in This Item:
T202003291.pdf Download
DOI
10.1038/s41418-020-0520-5
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Biochemistry and Molecular Biology (생화학-분자생물학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
Yonsei Authors
Kim, Hyun-Soo(김현수)
Chun, Kyung Hee(전경희) ORCID logo https://orcid.org/0000-0002-9867-7321
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/179728
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