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

Autor: Go Woon Kim, So Hee Kwon, So Yeon Kim, Jung Yoo, Ha Young Cho, Sang Wu Lee, Dong-Hoon Lee, Yu Hyun Jeon
Jazyk: angličtina
Rok vydání: 2020
Předmět:
0301 basic medicine
HPV
JQ1
Matrix metalloproteinase
HNSCC
Catalysis
Article
Gene Expression Regulation
Enzymologic
Metastasis
Inorganic Chemistry
BET inhibitor
lcsh:Chemistry
03 medical and health sciences
0302 clinical medicine
Antineoplastic Combined Chemotherapy Protocols
medicine
metastasis
Humans
Physical and Theoretical Chemistry
Neoplasm Metastasis
Molecular Biology
Protein kinase B
lcsh:QH301-705.5
Spectroscopy
Cell growth
Chemistry
Squamous Cell Carcinoma of Head and Neck
Organic Chemistry
ACY-241
General Medicine
Azepines
HDAC6
Triazoles
medicine.disease
Computer Science Applications
Squamous carcinoma
Neoplasm Proteins
Gene Expression Regulation
Neoplastic
stomatognathic diseases
030104 developmental biology
lcsh:Biology (General)
lcsh:QD1-999
Matrix Metalloproteinase 9
Apoptosis
Head and Neck Neoplasms
030220 oncology & carcinogenesis
Cancer research
Matrix Metalloproteinase 2
Zdroj: International Journal of Molecular Sciences
International Journal of Molecular Sciences, Vol 21, Iss 6873, p 6873 (2020)
Volume 21
Issue 18
ISSN: 1422-0067
Popis: Overexpression of histone deacetylase 6 (HDAC6) and bromodomain-containing protein 4 (BRD4) is related to aggressiveness of head and neck squamous carcinoma (HNSCC). Based on studies that HDAC6 and BRD4 are potential therapeutic targets of HNSCC, we hypothesized that the combination treatment of BET inhibitor JQ1 and HDAC6-selective inhibitor ACY-241 could exhibit synergistic anticancer effects in human papillomavirus (HPV)-positive and HPV-negative HNSCC cells. In this study, HNSCC cell growth and viability were measured by CCK-8 assay, apoptosis was analyzed by flow cytometry, and metastasis was studied by wound healing and transwell assays. Furthermore, immunoblotting is conducted to investigate proteins that modulate apoptosis or metastasis. Here, we report that the combination of ACY-241 and JQ1 shows synergistic cell growth inhibition, viability reduction, and apoptosis induction in HNSCC cells through inactivation of AKT and NF-&kappa
B signaling. Importantly, we demonstrate that combined treatment of ACY-241 and JQ1 synergistically suppresses TNF-&alpha
induced migration and invasion via dysregulating matrix metalloproteinase (MMP)-2, MMP-9, and MT1-MMP. Overall, the combination of ACY-241 and JQ1 significantly suppresses proliferation and metastasis in HPV-positive and HPV-negative HNSCC. Collectively, these findings suggest that the co-inhibition of BET and HDAC6 can be a new therapeutic strategy in HNSCC.
Databáze: OpenAIRE
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