Transforming activity of an oncoprotein-encoding circular RNA from human papillomavirus

Jiawei Zhao; Eunice E. Lee; Jiwoong Kim; Rong Yang; Bahir Chamseddin; Chunyang Ni; Elona Gusho; Yang Xie; Cheng Ming Chiang; Michael Buszczak; Xiaowei Zhan; Laimonis Laimins; Richard C. Wang

doi:10.1038/s41467-019-10246-5

Transforming activity of an oncoprotein-encoding circular RNA from human papillomavirus

Jiawei Zhao, Eunice E. Lee, Jiwoong Kim, Rong Yang, Bahir Chamseddin, Chunyang Ni, Elona Gusho, Yang Xie, Cheng Ming Chiang, Michael Buszczak, Xiaowei Zhan, Laimonis Laimins, Richard C. Wang^*

^*Corresponding author for this work

Microbiology-Immunology

Research output: Contribution to journal › Article › peer-review

197 Scopus citations

Abstract

Single-stranded circular RNAs (circRNAs), generated through ‘backsplicing’, occur more extensively than initially anticipated. The possible functions of the vast majority of circRNAs remain unknown. Virus-derived circRNAs have recently been described in gamma-herpesviruses. We report that oncogenic human papillomaviruses (HPVs) generate circRNAs, some of which encompass the E7 oncogene (circE7). HPV16 circE7 is detectable by both inverse RT-PCR and northern blotting of HPV16-transformed cells. CircE7 is N⁶-methyladenosine (m⁶A) modified, preferentially localized to the cytoplasm, associated with polysomes, and translated to produce E7 oncoprotein. Specific disruption of circE7 in CaSki cervical carcinoma cells reduces E7 protein levels and inhibits cancer cell growth both in vitro and in tumor xenografts. CircE7 is present in TCGA RNA-Seq data from HPV-positive cancers and in cell lines with only episomal HPVs. These results provide evidence that virus-derived, protein-encoding circular RNAs are biologically functional and linked to the transforming properties of some HPV.

Original language	English (US)
Article number	2300
Journal	Nature communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-10246-5
State	Published - Dec 1 2019

ASJC Scopus subject areas

Physics and Astronomy(all)
Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s41467-019-10246-5

Cite this

@article{d44ea854a82d4d87b4f4aa6aa11ca3a9,

title = "Transforming activity of an oncoprotein-encoding circular RNA from human papillomavirus",

abstract = "Single-stranded circular RNAs (circRNAs), generated through {\textquoteleft}backsplicing{\textquoteright}, occur more extensively than initially anticipated. The possible functions of the vast majority of circRNAs remain unknown. Virus-derived circRNAs have recently been described in gamma-herpesviruses. We report that oncogenic human papillomaviruses (HPVs) generate circRNAs, some of which encompass the E7 oncogene (circE7). HPV16 circE7 is detectable by both inverse RT-PCR and northern blotting of HPV16-transformed cells. CircE7 is N6-methyladenosine (m6A) modified, preferentially localized to the cytoplasm, associated with polysomes, and translated to produce E7 oncoprotein. Specific disruption of circE7 in CaSki cervical carcinoma cells reduces E7 protein levels and inhibits cancer cell growth both in vitro and in tumor xenografts. CircE7 is present in TCGA RNA-Seq data from HPV-positive cancers and in cell lines with only episomal HPVs. These results provide evidence that virus-derived, protein-encoding circular RNAs are biologically functional and linked to the transforming properties of some HPV.",

author = "Jiawei Zhao and Lee, {Eunice E.} and Jiwoong Kim and Rong Yang and Bahir Chamseddin and Chunyang Ni and Elona Gusho and Yang Xie and Chiang, {Cheng Ming} and Michael Buszczak and Xiaowei Zhan and Laimonis Laimins and Wang, {Richard C.}",

note = "Funding Information: We thank K. Ariizumi, J. Chung, J. Min, and J. Shay for use of hybridization equipment; A. Brown and N. Conrad for use of the Typhoon PhosphorImager and assistance with cell fractionation; and D. Castrillon for cervical carcinoma cells. Some RNA-Seq data was provided by TCGA, managed by the NCI and NHGRI (http://cancergenome.nih.gov). We thank N. Conrad, T. de Lange, J. Shay, P. Tsai, and K. Yancey for critically reviewing the manuscript. This work was supported by grants from the NCI (R01CA059655, R01CA142861) to L.L.; NIGMS (R01GM125812) to M.B.; NCI (R01CA103867), CPRIT (RP180349, RP190077), and Welch Foundation (I-1805) to C.-M.C.; NCI (P30CA142543, P50CA70907) for X.Z.; NIGMS (R01GM115473) to Y.X.; UT South-western Cary Council, Burroughs Wellcome Fund (1010978), ACS (RSG-18–058–01), and NIAMS (R01AR072655) to R.W. Publisher Copyright: {\textcopyright} 2019, The Author(s).",

year = "2019",

month = dec,

day = "1",

doi = "10.1038/s41467-019-10246-5",

language = "English (US)",

volume = "10",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

TY - JOUR

T1 - Transforming activity of an oncoprotein-encoding circular RNA from human papillomavirus

AU - Zhao, Jiawei

AU - Lee, Eunice E.

AU - Kim, Jiwoong

AU - Yang, Rong

AU - Chamseddin, Bahir

AU - Ni, Chunyang

AU - Gusho, Elona

AU - Xie, Yang

AU - Chiang, Cheng Ming

AU - Buszczak, Michael

AU - Zhan, Xiaowei

AU - Laimins, Laimonis

AU - Wang, Richard C.

N1 - Funding Information: We thank K. Ariizumi, J. Chung, J. Min, and J. Shay for use of hybridization equipment; A. Brown and N. Conrad for use of the Typhoon PhosphorImager and assistance with cell fractionation; and D. Castrillon for cervical carcinoma cells. Some RNA-Seq data was provided by TCGA, managed by the NCI and NHGRI (http://cancergenome.nih.gov). We thank N. Conrad, T. de Lange, J. Shay, P. Tsai, and K. Yancey for critically reviewing the manuscript. This work was supported by grants from the NCI (R01CA059655, R01CA142861) to L.L.; NIGMS (R01GM125812) to M.B.; NCI (R01CA103867), CPRIT (RP180349, RP190077), and Welch Foundation (I-1805) to C.-M.C.; NCI (P30CA142543, P50CA70907) for X.Z.; NIGMS (R01GM115473) to Y.X.; UT South-western Cary Council, Burroughs Wellcome Fund (1010978), ACS (RSG-18–058–01), and NIAMS (R01AR072655) to R.W. Publisher Copyright: © 2019, The Author(s).

PY - 2019/12/1

Y1 - 2019/12/1

N2 - Single-stranded circular RNAs (circRNAs), generated through ‘backsplicing’, occur more extensively than initially anticipated. The possible functions of the vast majority of circRNAs remain unknown. Virus-derived circRNAs have recently been described in gamma-herpesviruses. We report that oncogenic human papillomaviruses (HPVs) generate circRNAs, some of which encompass the E7 oncogene (circE7). HPV16 circE7 is detectable by both inverse RT-PCR and northern blotting of HPV16-transformed cells. CircE7 is N6-methyladenosine (m6A) modified, preferentially localized to the cytoplasm, associated with polysomes, and translated to produce E7 oncoprotein. Specific disruption of circE7 in CaSki cervical carcinoma cells reduces E7 protein levels and inhibits cancer cell growth both in vitro and in tumor xenografts. CircE7 is present in TCGA RNA-Seq data from HPV-positive cancers and in cell lines with only episomal HPVs. These results provide evidence that virus-derived, protein-encoding circular RNAs are biologically functional and linked to the transforming properties of some HPV.

AB - Single-stranded circular RNAs (circRNAs), generated through ‘backsplicing’, occur more extensively than initially anticipated. The possible functions of the vast majority of circRNAs remain unknown. Virus-derived circRNAs have recently been described in gamma-herpesviruses. We report that oncogenic human papillomaviruses (HPVs) generate circRNAs, some of which encompass the E7 oncogene (circE7). HPV16 circE7 is detectable by both inverse RT-PCR and northern blotting of HPV16-transformed cells. CircE7 is N6-methyladenosine (m6A) modified, preferentially localized to the cytoplasm, associated with polysomes, and translated to produce E7 oncoprotein. Specific disruption of circE7 in CaSki cervical carcinoma cells reduces E7 protein levels and inhibits cancer cell growth both in vitro and in tumor xenografts. CircE7 is present in TCGA RNA-Seq data from HPV-positive cancers and in cell lines with only episomal HPVs. These results provide evidence that virus-derived, protein-encoding circular RNAs are biologically functional and linked to the transforming properties of some HPV.

UR - http://www.scopus.com/inward/record.url?scp=85066936969&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85066936969&partnerID=8YFLogxK

U2 - 10.1038/s41467-019-10246-5

DO - 10.1038/s41467-019-10246-5

M3 - Article

C2 - 31127091

AN - SCOPUS:85066936969

SN - 2041-1723

VL - 10

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 2300

ER -

Transforming activity of an oncoprotein-encoding circular RNA from human papillomavirus

Abstract

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this