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HPV-mediated nuclear export of HP1γ drives cervical tumorigenesis by downregulation of p53
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...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429875/ https://www.ncbi.nlm.nih.gov/pubmed/32203172 http://dx.doi.org/10.1038/s41418-020-0520-5 |
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author | Yi, Sang Ah Lee, Dong Hoon Kim, Go Woon Ryu, Hyun-Wook Park, Jong Woo Lee, Jaecheol Han, Jihoon Park, Jee Hun Oh, Hwamok Lee, Jieun Choi, Junjeong Kim, Hyun-Soo Kang, Hyeok Gu Kim, Da-Hyun Chun, Kyung-Hee You, Jueng Soo Han, Jeung-Whan Kwon, So Hee |
author_facet | Yi, Sang Ah Lee, Dong Hoon Kim, Go Woon Ryu, Hyun-Wook Park, Jong Woo Lee, Jaecheol Han, Jihoon Park, Jee Hun Oh, Hwamok Lee, Jieun Choi, Junjeong Kim, Hyun-Soo Kang, Hyeok Gu Kim, Da-Hyun Chun, Kyung-Hee You, Jueng Soo Han, Jeung-Whan Kwon, So Hee |
author_sort | Yi, Sang Ah |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7429875 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-74298752020-08-19 HPV-mediated nuclear export of HP1γ drives cervical tumorigenesis by downregulation of p53 Yi, Sang Ah Lee, Dong Hoon Kim, Go Woon Ryu, Hyun-Wook Park, Jong Woo Lee, Jaecheol Han, Jihoon Park, Jee Hun Oh, Hwamok Lee, Jieun Choi, Junjeong Kim, Hyun-Soo Kang, Hyeok Gu Kim, Da-Hyun Chun, Kyung-Hee You, Jueng Soo Han, Jeung-Whan Kwon, So Hee Cell Death Differ Article 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. Nature Publishing Group UK 2020-03-23 2020-09 /pmc/articles/PMC7429875/ /pubmed/32203172 http://dx.doi.org/10.1038/s41418-020-0520-5 Text en © The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Yi, Sang Ah Lee, Dong Hoon Kim, Go Woon Ryu, Hyun-Wook Park, Jong Woo Lee, Jaecheol Han, Jihoon Park, Jee Hun Oh, Hwamok Lee, Jieun Choi, Junjeong Kim, Hyun-Soo Kang, Hyeok Gu Kim, Da-Hyun Chun, Kyung-Hee You, Jueng Soo Han, Jeung-Whan Kwon, So Hee HPV-mediated nuclear export of HP1γ drives cervical tumorigenesis by downregulation of p53 |
title | HPV-mediated nuclear export of HP1γ drives cervical tumorigenesis by downregulation of p53 |
title_full | HPV-mediated nuclear export of HP1γ drives cervical tumorigenesis by downregulation of p53 |
title_fullStr | HPV-mediated nuclear export of HP1γ drives cervical tumorigenesis by downregulation of p53 |
title_full_unstemmed | HPV-mediated nuclear export of HP1γ drives cervical tumorigenesis by downregulation of p53 |
title_short | HPV-mediated nuclear export of HP1γ drives cervical tumorigenesis by downregulation of p53 |
title_sort | hpv-mediated nuclear export of hp1γ drives cervical tumorigenesis by downregulation of p53 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429875/ https://www.ncbi.nlm.nih.gov/pubmed/32203172 http://dx.doi.org/10.1038/s41418-020-0520-5 |
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