J Cancer 2020; 11(2):364-373. doi:10.7150/jca.32436 This issue

Research Paper

Anti-oral Squamous Cell Carcinoma Effects of a Potent TAZ Inhibitor AR-42

Lingyu Su1,3,4, Si Wang1,3,4, Ting Yuan2,5, Xudong Xie1,3,4, Xiaoming Fu1,3,4, Ping Ji1,3,4✉, Lei Zhong2,5✉, Wenzhao Liu1,3,4✉

1. College of Stomatology, Chongqing Medical University, Chongqing, China;
2. Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China;
3. Chongqing Research Center for Oral Diseases and Biomedical Science, Chongqing, China;
4. Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, China;
5. Department of Pharmacy, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, Sichuan, China.

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Su L, Wang S, Yuan T, Xie X, Fu X, Ji P, Zhong L, Liu W. Anti-oral Squamous Cell Carcinoma Effects of a Potent TAZ Inhibitor AR-42. J Cancer 2020; 11(2):364-373. doi:10.7150/jca.32436. Available from https://www.jcancer.org/v11p0364.htm

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Oral squamous cell carcinoma (OSCC) is one of the most common malignancies worldwide. Although great progress has been made in diagnosis and treatment strategies in recent years, the 5-year survival rate of OSCC patients is still disappointingly low. Hence, there is still an unmet medical need for sufferers with OSCC. As a downstream effector of Hippo pathway, TAZ was up-regulated in multiple cancers including OSCC, and considered as an effective therapeutic target. In this study, we constructed a stable transfected cell line HEK293-TAZ to screen TAZ inhibitor using dual-luciferase reporter assay, and found a potential TAZ inhibitor AR-42. The results showed that AR-42 effectively suppressed the viability and proliferation of OSCC cells, and induced cellular apoptosis and cell cycle arrest in G2/M phase. Moreover, AR-42 potently inhibited cell invasion and the capacity of sphere-forming, as well as the expression of EMT and cancer stem cell related proteins in OSCC cells, exhibiting potential efficacy against OSCC metastasis and self-renewal of oral cancer stem cell. Further mechanism studies showed that AR-42 inhibited the total amount of TAZ and its paralog YAP mainly through blockade of TAZ/YAP transcription and promotion of TAZ/YAP protein degradation. Additionally, the inhibitory effect of AR-42 against TAZ, as well as its anti-OSCC activity could be also observed in SCC9 xenograft model. Taken together, AR-42 deserves to be further studied as a TAZ inhibitor, and is worthy to be further assessed as a potential drug candidate for OSCC treatment.

Keywords: oral squamous cell carcinoma, AR-42, histone deacetylase, cancer stem cell.