Three-dimensional chromatin analysis reveals Sp1 as a mediator to program and reprogram HPV-host epigenetic architecture in cervical cancer
Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved..
Human papillomavirus (HPV) is predominantly associated with HPV-related cancers, however, the precise mechanisms underlying the HPV-host epigenetic architectures in HPV carcinogenesis remain elusive. Here, we employed high-throughput chromosome conformation capture (Hi-C) to comprehensively map HPV16/18-host chromatin interactions. Our study identified the transcription factor Sp1 as a pivotal mediator in programming HPV-host interactions. By targeting Sp1, the active histone modifications (H3K27ac, H3K4me1, and H3K4me3) and the HPV-host chromatin interactions are reprogrammed, which leads to the downregulation of oncogenes located near the integration sites in both HPV (E6/E7) and the host genome (KLF5/MYC). Additionally, Sp1 inhibition led to the upregulation of immune checkpoint genes by reprogramming histone modifications in host cells. Notably, humanized patient-derived xenograft (PDX-HuHSC-NSG) models demonstrated that Sp1 inhibition promoted anti-PD-1 immunotherapy via remodeling the tumor immune microenvironment in cervical cancer. Moreover, single-cell transcriptomic analysis validated the enrichment of transcription factor Sp1 in epithelial cells of cervical cancer. In summary, our findings elucidate Sp1 as a key mediator involved in the programming and reprogramming of HPV-host epigenetic architecture. Inhibiting Sp1 with plicamycin may represent a promising therapeutic option for HPV-related carcinoma.
Medienart: |
E-Artikel |
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Erscheinungsjahr: |
2024 |
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Erschienen: |
2024 |
Enthalten in: |
Zur Gesamtaufnahme - volume:588 |
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Enthalten in: |
Cancer letters - 588(2024) vom: 28. Apr., Seite 216809 |
Sprache: |
Englisch |
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Beteiligte Personen: |
Cao, Canhui [VerfasserIn] |
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Links: |
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Anmerkungen: |
Date Completed 09.04.2024 Date Revised 12.04.2024 published: Print-Electronic Citation Status MEDLINE |
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doi: |
10.1016/j.canlet.2024.216809 |
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funding: |
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Förderinstitution / Projekttitel: |
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PPN (Katalog-ID): |
NLM369613686 |
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520 | |a Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved. | ||
520 | |a Human papillomavirus (HPV) is predominantly associated with HPV-related cancers, however, the precise mechanisms underlying the HPV-host epigenetic architectures in HPV carcinogenesis remain elusive. Here, we employed high-throughput chromosome conformation capture (Hi-C) to comprehensively map HPV16/18-host chromatin interactions. Our study identified the transcription factor Sp1 as a pivotal mediator in programming HPV-host interactions. By targeting Sp1, the active histone modifications (H3K27ac, H3K4me1, and H3K4me3) and the HPV-host chromatin interactions are reprogrammed, which leads to the downregulation of oncogenes located near the integration sites in both HPV (E6/E7) and the host genome (KLF5/MYC). Additionally, Sp1 inhibition led to the upregulation of immune checkpoint genes by reprogramming histone modifications in host cells. Notably, humanized patient-derived xenograft (PDX-HuHSC-NSG) models demonstrated that Sp1 inhibition promoted anti-PD-1 immunotherapy via remodeling the tumor immune microenvironment in cervical cancer. Moreover, single-cell transcriptomic analysis validated the enrichment of transcription factor Sp1 in epithelial cells of cervical cancer. In summary, our findings elucidate Sp1 as a key mediator involved in the programming and reprogramming of HPV-host epigenetic architecture. Inhibiting Sp1 with plicamycin may represent a promising therapeutic option for HPV-related carcinoma | ||
650 | 4 | |a Journal Article | |
650 | 4 | |a Cervical cancer | |
650 | 4 | |a Hi-C | |
650 | 4 | |a Human papillomavirus | |
650 | 4 | |a Immune checkpoint genes | |
650 | 4 | |a PD-1 immunotherapy | |
650 | 7 | |a Chromatin |2 NLM | |
650 | 7 | |a Oncogene Proteins, Viral |2 NLM | |
650 | 7 | |a Papillomavirus E7 Proteins |2 NLM | |
650 | 7 | |a Transcription Factors |2 NLM | |
650 | 7 | |a SP1 protein, human |2 NLM | |
700 | 1 | |a Xu, Qian |e verfasserin |4 aut | |
700 | 1 | |a Zhu, Zhixian |e verfasserin |4 aut | |
700 | 1 | |a Xu, Miaochun |e verfasserin |4 aut | |
700 | 1 | |a Wei, Ye |e verfasserin |4 aut | |
700 | 1 | |a Lin, Shitong |e verfasserin |4 aut | |
700 | 1 | |a Cheng, Sheng |e verfasserin |4 aut | |
700 | 1 | |a Zhi, Wenhua |e verfasserin |4 aut | |
700 | 1 | |a Hong, Ping |e verfasserin |4 aut | |
700 | 1 | |a Huang, Xingyu |e verfasserin |4 aut | |
700 | 1 | |a Lin, Da |e verfasserin |4 aut | |
700 | 1 | |a Cao, Gang |e verfasserin |4 aut | |
700 | 1 | |a Meng, Yifan |e verfasserin |4 aut | |
700 | 1 | |a Wu, Ping |e verfasserin |4 aut | |
700 | 1 | |a Peng, Ting |e verfasserin |4 aut | |
700 | 1 | |a Wei, Juncheng |e verfasserin |4 aut | |
700 | 1 | |a Ding, Wencheng |e verfasserin |4 aut | |
700 | 1 | |a Huang, Xiaoyuan |e verfasserin |4 aut | |
700 | 1 | |a Sung, WingKin |e verfasserin |4 aut | |
700 | 1 | |a Chen, Gang |e verfasserin |4 aut | |
700 | 1 | |a Ma, Ding |e verfasserin |4 aut | |
700 | 1 | |a Li, Guoliang |e verfasserin |4 aut | |
700 | 1 | |a Wu, Peng |e verfasserin |4 aut | |
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