ARID1A Hypermethylation Disrupts Transcriptional Homeostasis to Promote Squamous Cell Carcinoma Progression.
Qingyu LuoXiaowei WuWan ChangPengfei ZhaoXiaolin ZhuHongyan ChenYabing NanXuantong ZhouDan SuWenjie JiaoZhihua LiuPublished in: Cancer research (2020)
Switch/Sucrose Non-Fermentable (SWI/SNF) chromatin-remodeling complexes have a mutation rate of approximately 20% in human cancer, and ARID1A is the most frequently mutated component. However, some components of SWI/SNF complexes, including ARID1A, exhibit a very low mutation rate in squamous cell carcinoma (SCC), and their role in SCC remains unknown. Here, we demonstrate that the low expression of ARID1A in SCC is the result of promoter hypermethylation. Low levels of ARID1A were associated with a poor prognosis. ARID1A maintained transcriptional homeostasis through both direct and indirect chromatin-remodeling mechanisms. Depletion of ARID1A activated an oncogenic transcriptome that drove SCC progression. The anti-inflammatory natural product parthenolide was synthetically lethal to ARID1A-depleted SCC cells due to its inhibition of both HDAC1 and oncogenic signaling. These findings support the clinical application of parthenolide to treat patients with SCC with low ARID1A expression. SIGNIFICANCE: This study reveals novel inactivation mechanisms and tumor-suppressive roles of ARID1A in SCC and proposes parthenolide as an effective treatment for patients with SCC with low ARID1A expression.
Keyphrases
- poor prognosis
- squamous cell carcinoma
- transcription factor
- gene expression
- long non coding rna
- genome wide
- dna methylation
- dna damage
- endothelial cells
- radiation therapy
- lymph node metastasis
- signaling pathway
- single cell
- oxidative stress
- induced apoptosis
- papillary thyroid
- heat shock protein
- combination therapy
- wild type
- childhood cancer