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HDAC1 and HDAC2 Double Knockout Triggers Cell Apoptosis in Advanced Thyroid Cancer

Anaplastic thyroid carcinoma (ATC) and squamous thyroid carcinoma (STC) are both rare and advanced thyroid malignancies with a very poor prognosis and an average median survival time of 5 months and less than 20% of affected patients are alive 1 year after diagnosis. The clinical management of both...

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Autores principales: Lin, Ching-Ling, Tsai, Ming-Lin, Lin, Chun-Yu, Hsu, Kai-Wen, Hsieh, Wen-Shyang, Chi, Wei-Ming, Huang, Li-Chi, Lee, Chia-Hwa
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6359659/
https://www.ncbi.nlm.nih.gov/pubmed/30669676
http://dx.doi.org/10.3390/ijms20020454
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author Lin, Ching-Ling
Tsai, Ming-Lin
Lin, Chun-Yu
Hsu, Kai-Wen
Hsieh, Wen-Shyang
Chi, Wei-Ming
Huang, Li-Chi
Lee, Chia-Hwa
author_facet Lin, Ching-Ling
Tsai, Ming-Lin
Lin, Chun-Yu
Hsu, Kai-Wen
Hsieh, Wen-Shyang
Chi, Wei-Ming
Huang, Li-Chi
Lee, Chia-Hwa
author_sort Lin, Ching-Ling
collection PubMed
description Anaplastic thyroid carcinoma (ATC) and squamous thyroid carcinoma (STC) are both rare and advanced thyroid malignancies with a very poor prognosis and an average median survival time of 5 months and less than 20% of affected patients are alive 1 year after diagnosis. The clinical management of both ATC and STC is very similar because they are not particularly responsive to radiotherapy and chemotherapy. This inspired us to explore a novel and effective clinically approved therapy for ATC treatment. Histone deacetylase inhibitor (HDACi) drugs are recently FDA-approved drug for malignancies, especially for blood cell cancers. Therefore, we investigated whether an HDACi drug acts as an effective anticancer drug for advanced thyroid cancers. Cell viability analysis of panobinostat treatment demonstrated a significant IC50 of 0.075 µM on SW579 STC cells. In addition, panobinostat exposure activated histone acetylation and triggered cell death mainly through cell cycle arrest and apoptosis-related protein activation. Using CRISPR/Cas9 to knock out HDAC1 and HDAC2 genes in SW579 cells, we observed that the histone acetylation level and cell cycle arrest were enhanced without any impact on cell growth. Furthermore, HDAC1 and HDAC2 double knockout (KO) cells showed dramatic cell apoptosis activation compared to HDAC1 and HDAC2 individual KO cells. This suggests expressional and biofunctional compensation between HDAC1 and HDAC2 on SW579 cells. This study provides strong evidence that panobinostat can potentially be used in the clinic of advanced thyroid cancer patients.
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spelling pubmed-63596592019-02-06 HDAC1 and HDAC2 Double Knockout Triggers Cell Apoptosis in Advanced Thyroid Cancer Lin, Ching-Ling Tsai, Ming-Lin Lin, Chun-Yu Hsu, Kai-Wen Hsieh, Wen-Shyang Chi, Wei-Ming Huang, Li-Chi Lee, Chia-Hwa Int J Mol Sci Article Anaplastic thyroid carcinoma (ATC) and squamous thyroid carcinoma (STC) are both rare and advanced thyroid malignancies with a very poor prognosis and an average median survival time of 5 months and less than 20% of affected patients are alive 1 year after diagnosis. The clinical management of both ATC and STC is very similar because they are not particularly responsive to radiotherapy and chemotherapy. This inspired us to explore a novel and effective clinically approved therapy for ATC treatment. Histone deacetylase inhibitor (HDACi) drugs are recently FDA-approved drug for malignancies, especially for blood cell cancers. Therefore, we investigated whether an HDACi drug acts as an effective anticancer drug for advanced thyroid cancers. Cell viability analysis of panobinostat treatment demonstrated a significant IC50 of 0.075 µM on SW579 STC cells. In addition, panobinostat exposure activated histone acetylation and triggered cell death mainly through cell cycle arrest and apoptosis-related protein activation. Using CRISPR/Cas9 to knock out HDAC1 and HDAC2 genes in SW579 cells, we observed that the histone acetylation level and cell cycle arrest were enhanced without any impact on cell growth. Furthermore, HDAC1 and HDAC2 double knockout (KO) cells showed dramatic cell apoptosis activation compared to HDAC1 and HDAC2 individual KO cells. This suggests expressional and biofunctional compensation between HDAC1 and HDAC2 on SW579 cells. This study provides strong evidence that panobinostat can potentially be used in the clinic of advanced thyroid cancer patients. MDPI 2019-01-21 /pmc/articles/PMC6359659/ /pubmed/30669676 http://dx.doi.org/10.3390/ijms20020454 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Lin, Ching-Ling
Tsai, Ming-Lin
Lin, Chun-Yu
Hsu, Kai-Wen
Hsieh, Wen-Shyang
Chi, Wei-Ming
Huang, Li-Chi
Lee, Chia-Hwa
HDAC1 and HDAC2 Double Knockout Triggers Cell Apoptosis in Advanced Thyroid Cancer
title HDAC1 and HDAC2 Double Knockout Triggers Cell Apoptosis in Advanced Thyroid Cancer
title_full HDAC1 and HDAC2 Double Knockout Triggers Cell Apoptosis in Advanced Thyroid Cancer
title_fullStr HDAC1 and HDAC2 Double Knockout Triggers Cell Apoptosis in Advanced Thyroid Cancer
title_full_unstemmed HDAC1 and HDAC2 Double Knockout Triggers Cell Apoptosis in Advanced Thyroid Cancer
title_short HDAC1 and HDAC2 Double Knockout Triggers Cell Apoptosis in Advanced Thyroid Cancer
title_sort hdac1 and hdac2 double knockout triggers cell apoptosis in advanced thyroid cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6359659/
https://www.ncbi.nlm.nih.gov/pubmed/30669676
http://dx.doi.org/10.3390/ijms20020454
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