KDM6A-Mediated Expression of the Long Noncoding RNA DINO Causes TP53 Tumor Suppressor Stabilization in Human Papillomavirus 16 E7-Expressing Cells
Copyright © 2020 American Society for Microbiology..
Human papillomavirus 16 (HPV16) E7 has long been known to stabilize the tumor suppressor TP53. However, the molecular mechanism of TP53 stabilization by HPV16 E7 has remained obscure, and this stabilization can occur independently of the E2F-regulated MDM2 inhibitor p14ARF Here, we report that the damage-induced noncoding (DINO) lncRNA (DINOL) is the "missing link" between HPV16 E7 and increased TP53 levels. DINO levels are decreased in cells where TP53 is inactivated, either by HPV16 E6, by expression of a dominant negative TP53 minigene, or by TP53 depletion. DINO levels are increased in HPV16 E7-expressing cells. HPV16 E7 causes increased DINO expression independently of RB1 degradation and E2F1 activation. Similar to what is seen with the adjacent CDKN1A locus, DINO expression is regulated by the histone demethylase KDM6A. DINO stabilizes TP53 in HPV16 E7-expressing cells, and as it is a TP53 transcriptional target, DINO levels further increase. As with expression of other oncogenes, such as adenovirus E1A or MYC, HPV16 E7-expressing cells are sensitized to cell death under conditions of metabolic stress, which in the case of E7 has been linked to TP53 activation. Consistent with earlier studies, we show that HPV16 E7-expressing keratinocytes are highly sensitive to metabolic stress induced by starvation or the antidiabetic drug metformin. Sensitivity of HPV16 E7-expressing cells to metabolic stress is rescued by DINO depletion. Moreover, DINO depletion decreases sensitivity to the DNA damage-inducing chemotherapy agent doxorubicin. This work identifies DINO as a critical mediator of TP53 stabilization and activation in HPV16 E7-expressing cells.IMPORTANCE Viral oncoproteins, including HPV16 E6 and E7, have been instrumental in elucidating the activities of cellular signaling networks, including those governed by the TP53 tumor suppressor. Our study demonstrates that the long noncoding RNA DINO is the long-sought missing link between HPV16 E7 and elevated TP53 levels. Importantly, the TP53-stabilizing DINO plays a critical role in the cell death response of HPV16 E7-expressing cells to metabolic stress or DNA damage.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:94 |
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| Enthalten in: |
Journal of virology - 94(2020), 12 vom: 01. Juni |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Sharma, Surendra [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 18.11.2020 Date Revised 12.07.2021 published: Electronic-Print Citation Status MEDLINE |
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| doi: |
10.1128/JVI.02178-19 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM308543211 |
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| 100 | 1 | |a Sharma, Surendra |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a KDM6A-Mediated Expression of the Long Noncoding RNA DINO Causes TP53 Tumor Suppressor Stabilization in Human Papillomavirus 16 E7-Expressing Cells |
| 264 | 1 | |c 2020 | |
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| 500 | |a Date Completed 18.11.2020 | ||
| 500 | |a Date Revised 12.07.2021 | ||
| 500 | |a published: Electronic-Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2020 American Society for Microbiology. | ||
| 520 | |a Human papillomavirus 16 (HPV16) E7 has long been known to stabilize the tumor suppressor TP53. However, the molecular mechanism of TP53 stabilization by HPV16 E7 has remained obscure, and this stabilization can occur independently of the E2F-regulated MDM2 inhibitor p14ARF Here, we report that the damage-induced noncoding (DINO) lncRNA (DINOL) is the "missing link" between HPV16 E7 and increased TP53 levels. DINO levels are decreased in cells where TP53 is inactivated, either by HPV16 E6, by expression of a dominant negative TP53 minigene, or by TP53 depletion. DINO levels are increased in HPV16 E7-expressing cells. HPV16 E7 causes increased DINO expression independently of RB1 degradation and E2F1 activation. Similar to what is seen with the adjacent CDKN1A locus, DINO expression is regulated by the histone demethylase KDM6A. DINO stabilizes TP53 in HPV16 E7-expressing cells, and as it is a TP53 transcriptional target, DINO levels further increase. As with expression of other oncogenes, such as adenovirus E1A or MYC, HPV16 E7-expressing cells are sensitized to cell death under conditions of metabolic stress, which in the case of E7 has been linked to TP53 activation. Consistent with earlier studies, we show that HPV16 E7-expressing keratinocytes are highly sensitive to metabolic stress induced by starvation or the antidiabetic drug metformin. Sensitivity of HPV16 E7-expressing cells to metabolic stress is rescued by DINO depletion. Moreover, DINO depletion decreases sensitivity to the DNA damage-inducing chemotherapy agent doxorubicin. This work identifies DINO as a critical mediator of TP53 stabilization and activation in HPV16 E7-expressing cells.IMPORTANCE Viral oncoproteins, including HPV16 E6 and E7, have been instrumental in elucidating the activities of cellular signaling networks, including those governed by the TP53 tumor suppressor. Our study demonstrates that the long noncoding RNA DINO is the long-sought missing link between HPV16 E7 and elevated TP53 levels. Importantly, the TP53-stabilizing DINO plays a critical role in the cell death response of HPV16 E7-expressing cells to metabolic stress or DNA damage | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a DINO | |
| 650 | 4 | |a DINOL | |
| 650 | 4 | |a DNA damage | |
| 650 | 4 | |a E7 | |
| 650 | 4 | |a KDM6A | |
| 650 | 4 | |a TP53 | |
| 650 | 4 | |a chemotherapy | |
| 650 | 4 | |a human papillomavirus | |
| 650 | 4 | |a lncRNA | |
| 650 | 4 | |a long noncoding RNA | |
| 650 | 4 | |a metabolism | |
| 650 | 4 | |a metformin | |
| 650 | 7 | |a Antibiotics, Antineoplastic |2 NLM | |
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| 650 | 7 | |a E2F1 Transcription Factor |2 NLM | |
| 650 | 7 | |a E2F1 protein, human |2 NLM | |
| 650 | 7 | |a Hypoglycemic Agents |2 NLM | |
| 650 | 7 | |a MYC protein, human |2 NLM | |
| 650 | 7 | |a Papillomavirus E7 Proteins |2 NLM | |
| 650 | 7 | |a Proto-Oncogene Proteins c-myc |2 NLM | |
| 650 | 7 | |a RB1 protein, human |2 NLM | |
| 650 | 7 | |a RNA, Long Noncoding |2 NLM | |
| 650 | 7 | |a RNA, Small Interfering |2 NLM | |
| 650 | 7 | |a Retinoblastoma Binding Proteins |2 NLM | |
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| 650 | 7 | |a Tumor Suppressor Protein p53 |2 NLM | |
| 650 | 7 | |a oncogene protein E7, Human papillomavirus type 16 |2 NLM | |
| 650 | 7 | |a Doxorubicin |2 NLM | |
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| 856 | 4 | 0 | |u http://dx.doi.org/10.1128/JVI.02178-19 |3 Volltext |
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