Combination of ACY-241 and JQ1 Synergistically Suppresses Metastasis of HNSCC via Regulation of MMP-2 and MMP-9

Overexpression of histone deacetylase 6 (HDAC6) and bromodomain-containing protein 4 (BRD4) has been associated with the aggressiveness of head and neck squamous cell carcinoma (HNSCC). Given that HDAC6 and BRD4 have been identified as potential therapeutic targets in HNSCC, we hypothesized that combining the BET inhibitor JQ1 with the HDAC6-selective inhibitor ACY-241 could produce synergistic anticancer effects in both human papillomavirus (HPV)-positive and HPV-negative HNSCC cells. In this study, we assessed HNSCC cell growth and viability using the CCK-8 assay, analyzed apoptosis through flow cytometry, and examined metastasis using wound healing and transwell assays. Additionally, immunoblotting was performed to investigate proteins involved in apoptosis and metastasis. Our results demonstrate that the combination of ACY-241 and JQ1 synergistically inhibits cell growth, reduces viability, and induces apoptosis in HNSCC cells by inactivating the AKT and NF-κB signaling pathways. Notably, we show that this combined treatment also suppresses TNF-α-induced migration and invasion by dysregulating matrix metalloproteinase (MMP)-2, MMP-9, and MT1-MMP. Overall, the combination of ACY-241 and JQ1 significantly impedes proliferation and metastasis in both HPV-positive and HPV-negative HNSCC. These findings suggest that co-inhibition of BET and HDAC6 could represent a novel therapeutic strategy for HNSCC.