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

• Published in: Cell death and differentiation Vol. 27; no. 9; pp. 2537 - 2551
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.09.2020; Nature Publishing Group
• Subjects: 38/39; 38/89; 631/337/176; 64/60; 692/699/67/1244; 82/51; 82/80; Active Transport, Cell Nucleus; Animals; Apoptosis; Biochemistry; Biomedical and Life Sciences; Carcinogenesis - genetics; Carcinogenesis - pathology; Cell Biology; Cell Cycle Analysis; Cell Line, Tumor; Cell Nucleus - metabolism; Cervical cancer; Cervix; Chromosomal Proteins, Non-Histone - metabolism; Cytoplasm; Degradation; Down-Regulation - genetics; Doxycycline - pharmacology; E6 protein; Exportin 1 Protein; Female; Gene Expression Regulation, Neoplastic; Heterochromatin; Human papillomavirus; Karyopherins - metabolism; Life Sciences; Mice, Inbred BALB C; Mice, Nude; Models, Biological; Nuclear transport; Oncogene Proteins, Viral - metabolism; p53 Protein; Proteasomes; Protein Isoforms - metabolism; Protein transport; Proteins; Proteolysis; Receptors, Cytoplasmic and Nuclear - metabolism; Repressor Proteins - metabolism; Risk Factors; Stem Cells; Transcription; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumorigenesis; Ubiquitin-Conjugating Enzymes - genetics; Ubiquitin-Conjugating Enzymes - metabolism; Ubiquitination; Uterine Cervical Neoplasms - genetics; Uterine Cervical Neoplasms - pathology
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/s41418-020-0520-5

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.