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

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.

Histone deacetylase 1 and 2 drive differentiation and fusion of progenitor cells in human placental trophoblasts

“…In the current study, we found that cytotrophoblasts expressed HDAC1 and HDAC2, and that knockdown of either HDAC1 or HDAC2 did not impact syncytiotrophoblast formation. Interestingly, in cells with reduced HDAC1 or HDAC2, we observed increased expression of the paralogous protein, which is consistent with results in other studies 40,49,50 . However, inhibition of both HDAC1 and HDAC2 using FK228, or knockdown of both HDAC1 and HDAC2, inhibited cytotrophoblast differentiation, suggesting that HDAC1 and HDAC2 can compensate for each other during syncytiotrophoblast development.…”

The Roles of Histone Deacetylases and Their Inhibitors in Cancer Therapy

“…Class I-specific HDACi 4SC-202 globally increases both of H3K27ac and H3K4me3 levels around the TSS of genes, but notably decreases occupancy at proximal regions of TSS of genes such as SMAD family member 6 (SMAD6) and E2F transcription factor 8 (E2F8), which are associated with enhancer deactivation (Mishra et al, 2017). Panobinostat and Jamaladdin et al, 2014Heideman et al, 2013Lin et al, 2019Haberland et al, 2009Boucheron et al, 2014Preglej et al, 2020Montgomery et al, 2007Moresi et al, 2012;Dovey et al, Montgomery et al, 2008Lu et al, 2018Ho et al, 2020Bhaskara et al, 2008Bhaskara et al, 2010;Jiang and Hsieh, 2014Ji et al, 2019Hsu et al, 2015Phelps et al, 2016 Chen Impairs genome stability; embryonic lethality Vaquero et al, 2007;Wang et al, 2008 Represses angiogenesis Potente et al, 2007;Dioum et al, 2009;Lim et al, 2010 Impairs nicotinamide mononucleotide (NMN)-induced amelioration of liver fibrosis and NMN-dependent telomere integrity in premature aging mice Amano et al, 2019 Causes methionine restriction-induced lethality in mouse ESC Tang S. et al, 2017 Impairs myeloid-derived suppressor cells (MDSC) differentiation by disturbing glycolytic pathway Liu et al, 2014 Impairs various DNA repair Cohen et al, 2004;Yuan et al, 2007;Ming et al, 2010;Meng et al, 2020 Inhibits autophagy in MEFs Lee et al, 2008 Causes differentiation defects of mice ESC Tang Induces abnormal mitochondrial physiology, oxidative stress and genomic instability Kim et al, 2010 R...…”

HDAC Inhibition Induces PD-L1 Expression in a Novel Anaplastic Thyroid Cancer Cell Line

“…However, when the combined effect of valproic acid and paclitaxel was compared with paclitaxel alone in a phase II/III clinical trial no advantage was found [29]. Pan HDAC inhibitor panobinostat is an FDA approved drug in third line against multiple myeloma and it also has a strong cytotoxic effect in ATC and squamous thyroid carcinoma cells through induction cell cycle arrest and apoptosis [30,31].…”