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Computer-Aided Three-Dimensional Visualization in the Treatment of Locally Advanced Thyroid Cancer
Published on: June 9, 2023
HDAC1 and HDAC2 Double Knockout Triggers Cell Apoptosis in Advanced Thyroid Cancer
Ching-Ling Lin1,2, Ming-Lin Tsai3, Chun-Yu Lin4,5
1Department of Endocrinology and Metabolism, Cathay General Hospital, Taipei 10630, Taiwan. work5halfday@cgh.org.tw.
Abstract:
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.
Insights
Panobinostat, a histone deacetylase inhibitor (HDACi), shows promise for treating advanced thyroid cancers like anaplastic thyroid carcinoma (ATC) and squamous thyroid carcinoma (STC). This drug effectively induced cell death and apoptosis in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Anaplastic thyroid carcinoma (ATC) and squamous thyroid carcinoma (STC) are rare, aggressive thyroid cancers with poor prognoses.
- Current treatments like radiotherapy and chemotherapy show limited efficacy against these advanced thyroid malignancies.
Purpose of the Study:
- To investigate the potential of histone deacetylase inhibitors (HDACi) as an effective therapeutic strategy for advanced thyroid cancers.
- To evaluate the efficacy of panobinostat, an FDA-approved HDACi, in preclinical models of STC.
Main Methods:
- Cell viability assays were performed to determine the IC50 of panobinostat on SW579 STC cells.
- CRISPR/Cas9 gene editing was used to knock out HDAC1 and HDAC2 genes in SW579 cells.
- Analysis of histone acetylation, cell cycle arrest, and apoptosis-related protein activation was conducted.
Main Results:
- Panobinostat demonstrated significant cytotoxicity against SW579 STC cells with an IC50 of 0.075 µM.
- Treatment with panobinostat induced histone acetylation, cell cycle arrest, and apoptosis.
- Knockout of HDAC1 and HDAC2 genes enhanced histone acetylation and cell cycle arrest, with double knockout cells exhibiting increased apoptosis, suggesting functional compensation between these genes.
Conclusions:
- Panobinostat exhibits potent anticancer activity against advanced thyroid cancer cells in vitro.
- Targeting HDAC1 and HDAC2, possibly through HDACi like panobinostat, represents a promising therapeutic avenue for advanced thyroid cancer.
- This study provides a strong rationale for the clinical investigation of panobinostat in patients with advanced thyroid cancer.
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