TY - JOUR
T1 - Ecdysoneless Protein Regulates Viral and Cellular mRNA Splicing to Promote Cervical Oncogenesis
AU - Mirza, Sameer
AU - Kalluchi, Achyuth
AU - Raza, Mohsin
AU - Saleem, Irfana
AU - Mohapatra, Bhopal
AU - Pal, Dhananjaya
AU - Ouellette, Michel M.
AU - Qiu, Fang
AU - Yu, Lulu
AU - Lobanov, Alexei
AU - Zheng, Zhi Ming
AU - Zhang, Ying
AU - Alsaleem, Mansour A.
AU - Rakha, Emad A.
AU - Band, Hamid
AU - Rowley, M. Jordan
AU - Band, Vimla
N1 - Funding Information:
F. Qiu reports grants from NIH and grants from DOD during the conduct of the study. H. Band reports grants from Department of Defense during the conduct of the study; and grants from Department of Defense outside the submitted work. V. Band reports grants from NIH and grants from Department of Defense Breast Cancer Program during the conduct of the study. No disclosures were reported by the other authors.
Funding Information:
We would like to acknowledge the University of Nebraska Medical Center Genomics and Bioinformatics Core facilities for their technical support of this work. This work was supported by the NIH grant R21CA241055 (to V. Band); Department of Defense grants W81XWH-17–1-0616 and W81XWH-20–1-0058 (to H. Band) and W81XWH-20–1-0546 (to V. Band); Nebraska Initiative Grant (to V. Band); a NIH grant R00GM127671 (to M.J. Rowley). S. Mirza is supported by Nebraska Research Initiative Grant. Support for the University of Nebraska Medical Center Genomics was from NCI Support Grant P30CA036727 to the Fred and Pamela Buffett Cancer Center.
Publisher Copyright:
© 2021 The Authors.
PY - 2022/2
Y1 - 2022/2
N2 - High-risk human papillomaviruses (HPV), exemplified by HPV16/18, are causally linked to human cancers of the anogenital tract, skin, and upper aerodigestive tract. Previously, we identified Ecdysoneless (ECD) protein, the human homolog of the Drosophila ecdysoneless gene, as a novel HPV16 E6–interacting protein. Here, we show that ECD, through its C-terminal region, selectively binds to high-risk but not to low-risk HPV E6 proteins. We demonstrate that ECD is overexpressed in cervical and head and neck squamous cell carcinoma (HNSCC) cell lines as well as in tumor tissues. Using The Cancer Genome Atlas dataset, we show that ECD mRNA overexpression predicts shorter survival in patients with cervical and HNSCC. We demonstrate that ECD knockdown in cervical cancer cell lines led to impaired oncogenic behavior, and ECD co-overexpression with E7 immortalized primary human keratinocytes. RNA-sequencing analyses of SiHa cells upon ECD knockdown showed to aberrations in E6/E7 RNA splicing, as well as RNA splicing of several HPV oncogenesis–linked cellular genes, including splicing of components of mRNA splicing machinery itself. Taken together, our results support a novel role of ECD in viral and cellular mRNA splicing to support HPV-driven oncogenesis.
AB - High-risk human papillomaviruses (HPV), exemplified by HPV16/18, are causally linked to human cancers of the anogenital tract, skin, and upper aerodigestive tract. Previously, we identified Ecdysoneless (ECD) protein, the human homolog of the Drosophila ecdysoneless gene, as a novel HPV16 E6–interacting protein. Here, we show that ECD, through its C-terminal region, selectively binds to high-risk but not to low-risk HPV E6 proteins. We demonstrate that ECD is overexpressed in cervical and head and neck squamous cell carcinoma (HNSCC) cell lines as well as in tumor tissues. Using The Cancer Genome Atlas dataset, we show that ECD mRNA overexpression predicts shorter survival in patients with cervical and HNSCC. We demonstrate that ECD knockdown in cervical cancer cell lines led to impaired oncogenic behavior, and ECD co-overexpression with E7 immortalized primary human keratinocytes. RNA-sequencing analyses of SiHa cells upon ECD knockdown showed to aberrations in E6/E7 RNA splicing, as well as RNA splicing of several HPV oncogenesis–linked cellular genes, including splicing of components of mRNA splicing machinery itself. Taken together, our results support a novel role of ECD in viral and cellular mRNA splicing to support HPV-driven oncogenesis.
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U2 - 10.1158/1541-7786.MCR-21-0567
DO - 10.1158/1541-7786.MCR-21-0567
M3 - Article
C2 - 34670863
AN - SCOPUS:85124052526
SN - 1541-7786
VL - 20
SP - 305
EP - 318
JO - Cell Growth and Differentiation
JF - Cell Growth and Differentiation
IS - 2
ER -