Multiple ETS Factors Participate in the Transcriptional Control of <i>TERT</i> Mutant Promoter in Thyroid Cancers
Hotspot mutations in the <i>TERT</i> (telomerase reverse transcriptase) gene are key determinants of thyroid cancer progression. <i>TERT</i> promoter mutations (TPM) create de novo consensus binding sites for the ETS (“E26 transformation specific”) family of transcription fac...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-01-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/14/2/357 |
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| author | Caitlin E. M. Thornton Jingzhu Hao Prasanna P. Tamarapu Iñigo Landa |
| author_facet | Caitlin E. M. Thornton Jingzhu Hao Prasanna P. Tamarapu Iñigo Landa |
| author_sort | Caitlin E. M. Thornton |
| collection | DOAJ |
| description | Hotspot mutations in the <i>TERT</i> (telomerase reverse transcriptase) gene are key determinants of thyroid cancer progression. <i>TERT</i> promoter mutations (TPM) create de novo consensus binding sites for the ETS (“E26 transformation specific”) family of transcription factors. In this study, we systematically knocked down each of the 20 ETS factors expressed in thyroid tumors and screened their effects on TERT expression in seven thyroid cancer cell lines with defined TPM status. We observed that, unlike in other TPM-carrying cancers such as glioblastomas, ETS factor GABPA does not unambiguously regulate transcription from the <i>TERT</i> mutant promoter in thyroid specimens. In fact, multiple members of the ETS family impact <i>TERT</i> expression, and they typically do so in a mutation-independent manner. In addition, we observe that partial inhibition of MAPK, a central pathway in thyroid cancer transformation, is more effective at suppressing <i>TERT</i> transcription in the absence of TPMs. Taken together, our results show a more complex scenario of <i>TERT</i> regulation in thyroid cancers compared with other lineages and suggest that compensatory mechanisms by ETS and other regulators likely exist and advocate for the need for a more comprehensive understanding of the mechanisms of <i>TERT</i> deregulation in thyroid tumors before eventually exploring TPM-specific therapeutic strategies. |
| first_indexed | 2024-03-10T01:47:00Z |
| format | Article |
| id | doaj.art-3f5bc9ce360a44dca0e785d98a8d2149 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T01:47:00Z |
| publishDate | 2022-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-3f5bc9ce360a44dca0e785d98a8d21492023-11-23T13:13:44ZengMDPI AGCancers2072-66942022-01-0114235710.3390/cancers14020357Multiple ETS Factors Participate in the Transcriptional Control of <i>TERT</i> Mutant Promoter in Thyroid CancersCaitlin E. M. Thornton0Jingzhu Hao1Prasanna P. Tamarapu2Iñigo Landa3Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USADivision of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USAHuman Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USADivision of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USAHotspot mutations in the <i>TERT</i> (telomerase reverse transcriptase) gene are key determinants of thyroid cancer progression. <i>TERT</i> promoter mutations (TPM) create de novo consensus binding sites for the ETS (“E26 transformation specific”) family of transcription factors. In this study, we systematically knocked down each of the 20 ETS factors expressed in thyroid tumors and screened their effects on TERT expression in seven thyroid cancer cell lines with defined TPM status. We observed that, unlike in other TPM-carrying cancers such as glioblastomas, ETS factor GABPA does not unambiguously regulate transcription from the <i>TERT</i> mutant promoter in thyroid specimens. In fact, multiple members of the ETS family impact <i>TERT</i> expression, and they typically do so in a mutation-independent manner. In addition, we observe that partial inhibition of MAPK, a central pathway in thyroid cancer transformation, is more effective at suppressing <i>TERT</i> transcription in the absence of TPMs. Taken together, our results show a more complex scenario of <i>TERT</i> regulation in thyroid cancers compared with other lineages and suggest that compensatory mechanisms by ETS and other regulators likely exist and advocate for the need for a more comprehensive understanding of the mechanisms of <i>TERT</i> deregulation in thyroid tumors before eventually exploring TPM-specific therapeutic strategies.https://www.mdpi.com/2072-6694/14/2/357<i>TERT</i> promoter mutationsETS factorsthyroid cancertranscriptional regulationMAPK signaling |
| spellingShingle | Caitlin E. M. Thornton Jingzhu Hao Prasanna P. Tamarapu Iñigo Landa Multiple ETS Factors Participate in the Transcriptional Control of <i>TERT</i> Mutant Promoter in Thyroid Cancers Cancers <i>TERT</i> promoter mutations ETS factors thyroid cancer transcriptional regulation MAPK signaling |
| title | Multiple ETS Factors Participate in the Transcriptional Control of <i>TERT</i> Mutant Promoter in Thyroid Cancers |
| title_full | Multiple ETS Factors Participate in the Transcriptional Control of <i>TERT</i> Mutant Promoter in Thyroid Cancers |
| title_fullStr | Multiple ETS Factors Participate in the Transcriptional Control of <i>TERT</i> Mutant Promoter in Thyroid Cancers |
| title_full_unstemmed | Multiple ETS Factors Participate in the Transcriptional Control of <i>TERT</i> Mutant Promoter in Thyroid Cancers |
| title_short | Multiple ETS Factors Participate in the Transcriptional Control of <i>TERT</i> Mutant Promoter in Thyroid Cancers |
| title_sort | multiple ets factors participate in the transcriptional control of i tert i mutant promoter in thyroid cancers |
| topic | <i>TERT</i> promoter mutations ETS factors thyroid cancer transcriptional regulation MAPK signaling |
| url | https://www.mdpi.com/2072-6694/14/2/357 |
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