Expression of the Long Noncoding RNA DINO in Human Papillomavirus-Positive Cervical Cancer Cells Reactivates the Dormant TP53 Tumor Suppressor through ATM/CHK2 Signaling

ABSTRACT Tumor cells overcome the cytostatic and cytotoxic restraints of TP53 tumor suppressor signaling through a variety of mechanisms. High-risk human papillomavirus (HPV)-positive tumor cells retain wild-type TP53 because the HPV E6/UBE3A ubiquitin ligase complex targets TP53 for proteasomal deg...

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Autores principales:	Surendra Sharma, Karl Munger
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	human papillomaviruses cervical cancer lncRNA DINO DINOL TP53 Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/748f3bb345ec42d691c138130ce911f5
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spelling	oai:doaj.org-article:748f3bb345ec42d691c138130ce911f52021-11-15T15:56:46ZExpression of the Long Noncoding RNA DINO in Human Papillomavirus-Positive Cervical Cancer Cells Reactivates the Dormant TP53 Tumor Suppressor through ATM/CHK2 Signaling10.1128/mBio.01190-202150-7511https://doaj.org/article/748f3bb345ec42d691c138130ce911f52020-06-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01190-20https://doaj.org/toc/2150-7511ABSTRACT Tumor cells overcome the cytostatic and cytotoxic restraints of TP53 tumor suppressor signaling through a variety of mechanisms. High-risk human papillomavirus (HPV)-positive tumor cells retain wild-type TP53 because the HPV E6/UBE3A ubiquitin ligase complex targets TP53 for proteasomal degradation. While restoration of TP53 in tumor cells holds great promise for cancer therapy, attempts to functionally restore the dormant TP53 tumor suppressor in HPV-positive cancer cells by inhibiting the HPV E6/UBE3A ubiquitin ligase complex have not yet been successful. The damage-induced long noncoding RNA, DINO (DINOL), is a TP53 transcriptional target that has been reported to bind to and stabilize TP53, thereby amplifying TP53 signaling. We show that HPV-positive cervical carcinoma cells contain low levels of DINO because of HPV E6/UBE3A-mediated TP53 degradation. Acute DINO expression overrides HPV16 E6/UBE3A-mediated TP53 degradation, causing TP53 stabilization and increased expression of TP53 transcriptional target genes. This causes a marked sensitization to chemotherapy agents and renders cells vulnerable to metabolic stress. Acute DINO expression in HPV-positive cervical cancer cells induces hallmarks of DNA damage response signaling, and TP53 activation involves ATM/CHK2 signaling. DINO upregulation in response to DNA damage is independent of ATM/CHK2 and can occur in cancer cells that express mutant TP53. IMPORTANCE Functional restoration of the TP53 tumor suppressor holds great promise for anticancer therapy. Current strategies are focused on modulating TP53 regulatory proteins. Long noncoding RNAs (lncRNAs) have emerged as important regulators of TP53 as well as modulators of downstream tumor-suppressive transcriptional responses. Unlike many other cancer types, human papillomavirus (HPV)-positive cancer cells retain wild-type TP53 that is rendered dysfunctional by the viral E6 protein. We show that acute expression of the damage-induced long noncoding RNA, DINO, a known TP53 transcriptional target and functional modulator, causes TP53 reactivation in HPV-positive cervical cancer cells. This causes increased vulnerability to standard chemotherapeutics as well as biguanide compounds that cause metabolic stress. Hence, strategies that target DINO may be useful for restoring TP53 tumor suppressor activity in HPV-positive cancers and other tumor types that retain wild-type TP53.Surendra SharmaKarl MungerAmerican Society for Microbiologyarticlehuman papillomavirusescervical cancerlncRNADINODINOLTP53MicrobiologyQR1-502ENmBio, Vol 11, Iss 3 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	human papillomaviruses cervical cancer lncRNA DINO DINOL TP53 Microbiology QR1-502
spellingShingle	human papillomaviruses cervical cancer lncRNA DINO DINOL TP53 Microbiology QR1-502 Surendra Sharma Karl Munger Expression of the Long Noncoding RNA DINO in Human Papillomavirus-Positive Cervical Cancer Cells Reactivates the Dormant TP53 Tumor Suppressor through ATM/CHK2 Signaling
description	ABSTRACT Tumor cells overcome the cytostatic and cytotoxic restraints of TP53 tumor suppressor signaling through a variety of mechanisms. High-risk human papillomavirus (HPV)-positive tumor cells retain wild-type TP53 because the HPV E6/UBE3A ubiquitin ligase complex targets TP53 for proteasomal degradation. While restoration of TP53 in tumor cells holds great promise for cancer therapy, attempts to functionally restore the dormant TP53 tumor suppressor in HPV-positive cancer cells by inhibiting the HPV E6/UBE3A ubiquitin ligase complex have not yet been successful. The damage-induced long noncoding RNA, DINO (DINOL), is a TP53 transcriptional target that has been reported to bind to and stabilize TP53, thereby amplifying TP53 signaling. We show that HPV-positive cervical carcinoma cells contain low levels of DINO because of HPV E6/UBE3A-mediated TP53 degradation. Acute DINO expression overrides HPV16 E6/UBE3A-mediated TP53 degradation, causing TP53 stabilization and increased expression of TP53 transcriptional target genes. This causes a marked sensitization to chemotherapy agents and renders cells vulnerable to metabolic stress. Acute DINO expression in HPV-positive cervical cancer cells induces hallmarks of DNA damage response signaling, and TP53 activation involves ATM/CHK2 signaling. DINO upregulation in response to DNA damage is independent of ATM/CHK2 and can occur in cancer cells that express mutant TP53. IMPORTANCE Functional restoration of the TP53 tumor suppressor holds great promise for anticancer therapy. Current strategies are focused on modulating TP53 regulatory proteins. Long noncoding RNAs (lncRNAs) have emerged as important regulators of TP53 as well as modulators of downstream tumor-suppressive transcriptional responses. Unlike many other cancer types, human papillomavirus (HPV)-positive cancer cells retain wild-type TP53 that is rendered dysfunctional by the viral E6 protein. We show that acute expression of the damage-induced long noncoding RNA, DINO, a known TP53 transcriptional target and functional modulator, causes TP53 reactivation in HPV-positive cervical cancer cells. This causes increased vulnerability to standard chemotherapeutics as well as biguanide compounds that cause metabolic stress. Hence, strategies that target DINO may be useful for restoring TP53 tumor suppressor activity in HPV-positive cancers and other tumor types that retain wild-type TP53.
format	article
author	Surendra Sharma Karl Munger
author_facet	Surendra Sharma Karl Munger
author_sort	Surendra Sharma
title	Expression of the Long Noncoding RNA DINO in Human Papillomavirus-Positive Cervical Cancer Cells Reactivates the Dormant TP53 Tumor Suppressor through ATM/CHK2 Signaling
title_short	Expression of the Long Noncoding RNA DINO in Human Papillomavirus-Positive Cervical Cancer Cells Reactivates the Dormant TP53 Tumor Suppressor through ATM/CHK2 Signaling
title_full	Expression of the Long Noncoding RNA DINO in Human Papillomavirus-Positive Cervical Cancer Cells Reactivates the Dormant TP53 Tumor Suppressor through ATM/CHK2 Signaling
title_fullStr	Expression of the Long Noncoding RNA DINO in Human Papillomavirus-Positive Cervical Cancer Cells Reactivates the Dormant TP53 Tumor Suppressor through ATM/CHK2 Signaling
title_full_unstemmed	Expression of the Long Noncoding RNA DINO in Human Papillomavirus-Positive Cervical Cancer Cells Reactivates the Dormant TP53 Tumor Suppressor through ATM/CHK2 Signaling
title_sort	expression of the long noncoding rna dino in human papillomavirus-positive cervical cancer cells reactivates the dormant tp53 tumor suppressor through atm/chk2 signaling
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/748f3bb345ec42d691c138130ce911f5
work_keys_str_mv	AT surendrasharma expressionofthelongnoncodingrnadinoinhumanpapillomaviruspositivecervicalcancercellsreactivatesthedormanttp53tumorsuppressorthroughatmchk2signaling AT karlmunger expressionofthelongnoncodingrnadinoinhumanpapillomaviruspositivecervicalcancercellsreactivatesthedormanttp53tumorsuppressorthroughatmchk2signaling
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Expression of the Long Noncoding RNA DINO in Human Papillomavirus-Positive Cervical Cancer Cells Reactivates the Dormant TP53 Tumor Suppressor through ATM/CHK2 Signaling

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