HPV integration hijacks and multimerizes a cellular enhancer to generate a viral-cellular super-enhancer that drives high viral oncogene expression

Warburton, Alix; Redmond, Catherine J.; Dooley, Katharine E.; Fu, Haiqing; Gillison, Maura L.; Akagi, Keiko; Symer, David E.; Aladjem, Mirit I.; McBride, Alison A.

doi:10.1371/journal.pgen.1007179

“…Currently, viral infection is identified to be a chief biological pathogenic factor to facilitate oncogenic SE and seRNA generation. Integration of human papillomavirus (HPV) genomes into cellular chromatin is frequent in HPV-associated cancers [61]. Tandemly integrated HPV16 could result in viral-cellular SE element formation [62], which mediates seRNA HOTAIR transcription and enhances E6 and E7 expression, causing cervical cancer pathogenesis [63].…”

Section: Oncogenic Serna Formationmentioning

confidence: 99%

“…It could be speculated that CCAT1-L may regulate MYC expression by interacting with CTCF, which stabilizes long-range chromatin interactions of MYC promoter with MYC-335 or interaction of MYC-335 with MYC-515 [32]. Additionally, T-ALLrelated TAL1 [16], Ewing sarcoma-related MEIS1 [100], hepatocellular carcinoma (HCC)-correlated sphingosine kinase 1 (SPHK1) [101], HPV-induced E6 and E7 [61], oral squamous cell carcinoma (OSCC)-associated PAK4, RUNX1, DNAJB1, SREBF2 and YAP1 [102] are correspondingly regulated by oncogenic SE, and promote cancer development. and PD-L1 to inhibit immunity.…”

Section: Serna Promotes Oncogene Expressionmentioning

confidence: 99%

Oncogenic seRNA functional activation: a novel mechanism of tumorigenesis

Tan

¹

,

Li

²

,

Tang

³

2020

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seRNA is a noncoding RNA (ncRNA) transcribed from active super-enhancer (SE), through which SE exerts biological functions and participates in various physiological and pathological processes. seRNA recruits cofactor, RNA polymerase II and mediator to constitute and stabilize chromatin loop SE and promoter region, which regulates target genes transcription. In tumorigenesis, DNA insertion, deletion, translocation, focal amplification and carcinogen factor mediate oncogenic SE generation, meanwhile, oncogenic SE transcribes into tumor-related seRNA, termed as oncogenic seRNA. Oncogenic seRNA participates in tumorigenesis through activating various signal-pathways. The recent reports showed that oncogenic seRNA implicates in a widespread range of cytopathological processes in cancer progression including cell proliferation, apoptosis, autophagy, epithelial-mesenchymal transition, extracellular matrix stiffness and angiogenesis. In this article, we comprehensively summarized seRNA's characteristics and functions, and emphatically introduced inducible formation of oncogenic seRNA and its functional mechanisms. Lastly, some research strategies on oncogenic seRNA were introduced, and the perspectives on cancer therapy that targets oncogenic seRNA were also discussed.

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“…These initiate at viral promoters and proceed into the host genes. Viral enhancers may also activate flanking oncogene promoters …”

Section: Introductionmentioning

confidence: 99%

“…Viral enhancers may also activate flanking oncogene promoters. [38][39][40] Approaches to detect integrated viral DNA have included RNA sequencing (RNAseq) to detect fusion transcripts, and DNA sequencing strategies including PCR or hybridization capture to identify the junctions between inserted HPV and human genome DNA. [20][21][22][23] However, in most instances only one of the two junctions between the linear HPV DNA fragment and human DNA was identified, and structural characterization of the inserted viral DNA was incomplete or inferred.…”

Section: Introductionmentioning

confidence: 99%

Insertional oncogenesis by HPV70 revealed by multiple genomic analyses in a clinically HPV‐negative cervical cancer

Arsdale

¹

,

Patterson

²

,

Maggi

³

et al. 2019

Genes Chromosomes & Cancer

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Cervical carcinogenesis, the second leading cause of cancer death in women worldwide, is caused by multiple types of human papillomaviruses (HPVs). To investigate a possible role for HPV in a cervical carcinoma that was HPV‐negative by PCR testing, we performed HPV DNA hybridization capture plus massively parallel sequencing. This detected a subgenomic, URR‐E6‐E7‐E1 segment of HPV70 DNA, a type not generally associated with cervical cancer, inserted in an intron of the B‐cell lymphoma/leukemia 11B (BCL11B) gene in the human genome. Long range DNA sequencing confirmed the virus and flanking BCL11B DNA structures including both insertion junctions. Global transcriptomic analysis detected multiple, alternatively spliced, HPV70‐BCL11B, fusion transcripts with fused open reading frames. The insertion and fusion transcripts were present in an intraepithelial precursor phase of tumorigenesis. These results suggest oncogenicity of HPV70, identify novel BCL11B variants with potential oncogenic implications, and underscore the advantages of thorough genomic analyses to elucidate insights into HPV‐associated tumorigenesis.

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“…These initiate at viral promoters and proceed into the host genes. Viral enhancers may also activate flanking oncogene promoters (38)(39)(40).…”

Section: Introductionmentioning

confidence: 99%

Insertional oncogenesis by HPV70 revealed by multiple genomic analyses in a clinically HPV-negative cervical cancer

Arsdale

¹

,

Patterson

²

,

Maggi

³

et al. 2019

Preprint

0

View full text Add to dashboard Cite

Cervical carcinogenesis, the second leading cause of cancer death in women worldwide, is caused by multiple types of human papillomaviruses (HPVs). To investigate a possible role for HPV in a cervical carcinoma that was HPV-negative by PCR testing, we performed HPV DNA hybridization capture plus massively parallel sequencing. This detected a subgenomic, URR-E6-E7-E1 segment of HPV70 DNA, a type not generally associated with cervical cancer, inserted in an intron of the B-cell lymphoma/leukemia 11B (BCL11B) gene in the human genome. Long range DNA sequencing confirmed the virus and flanking BCL11B DNA structures including both insertion junctions. Global transcriptomic analysis detected multiple, alternatively spliced, HPV70-BCL11B, fusion transcripts with fused open reading frames. The insertion and fusion transcripts were present in an intraepithelial precursor phase of tumorigenesis. These results suggest oncogenicity of HPV70, identify novel BCL11B variants with potential oncogenic implications, and underscore the advantages of thorough genomic analyses to elucidate insights into HPV-associated tumorigenesis. Statement of SignificanceMultiple HPV types have been defined as high risk for cancer causation. However, genomic analyses applied here detected a non-high risk HPV in a carcinoma that was HPV negative, and elucidated virally-associated tumorigenic genetic events. This stresses the importance of thorough genomic analyses for elucidating genetic processes in HPV-associated tumorigenesis. Author SummaryCervical cancer is the second leading cause of cancer death in women worldwide. Most cervical cancers are caused by one of 15 high risk types of human papilloma viruses (HPVs), although hundreds of types of HPVs exist. We used a series of contemporary genomics analyses to examine a cervical cancer that was clinically determined to be HPV-negative.These detected DNA of HPV70, an HPV type not considered to be high risk, in the tumor.Approximately half of the HPV70 DNA genome was present including the viral E6 and E7 oncogenes. Moreover, the viral DNA was inserted into the BCL11B gene in the human genome. BCL11B is known to be mutated in certain human cancers. The HPV70 DNA interacted with the human BCL11B gene to produce altered forms of RNA encoding unusual, truncated forms of the BCL11B protein. These results strongly implicate HPV70 as being oncogenic, suggest that this tumor was caused by a combination of viral oncogenes plus the virally-activated human BCL11B gene, demonstrate novel truncated BCL11B variants with oncogenic implications, and underscore the advantages of thorough genomic analyses to elucidate HPV tumorigenesis insights

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HPV integration hijacks and multimerizes a cellular enhancer to generate a viral-cellular super-enhancer that drives high viral oncogene expression

Cited by 87 publications

References 55 publications

Oncogenic seRNA functional activation: a novel mechanism of tumorigenesis

Oncogenic seRNA functional activation: a novel mechanism of tumorigenesis

Insertional oncogenesis by HPV70 revealed by multiple genomic analyses in a clinically HPV‐negative cervical cancer

Insertional oncogenesis by HPV70 revealed by multiple genomic analyses in a clinically HPV-negative cervical cancer

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