Combined class I histone deacetylase and mTORC1/C2 inhibition suppresses the initiation and recurrence of oral squamous cell carcinomas by repressing SOX2

• Published in: Cancer letters Vol. 454; pp. 108 - 119
• Main Authors: Liang, Xueyi, Deng, Miao, Zhang, Chi, Ping, Fan, Wang, Hongfei, Wang, Yun, Fan, Zhaona, Ren, Xianyue, Tao, Xiaoan, Wu, Tong, Xu, Jian, Cheng, Bin, Xia, Juan
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 10-07-2019; Elsevier Limited
• Subjects: 4SC-202; Animals; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Apoptosis; Benzamides - administration & dosage; Benzamides - pharmacology; Benzoxazoles - administration & dosage; Benzoxazoles - pharmacology; Cancer stem cells (CSCs); Carcinogenesis; Cell cycle; Cell growth; Cell viability; Chemoresistance; Combined treatment; Drug resistance; Drug Synergism; Female; Gene expression; Genomics; Histone deacetylase; Histone Deacetylase 1 - antagonists & inhibitors; Humans; Inhibition; INK128; Mechanistic Target of Rapamycin Complex 1 - antagonists & inhibitors; Mechanistic Target of Rapamycin Complex 1 - metabolism; Mechanistic Target of Rapamycin Complex 2 - antagonists & inhibitors; Mechanistic Target of Rapamycin Complex 2 - metabolism; Medical prognosis; Metastases; Metastasis; Mice; Mice, Inbred BALB C; Mouth Neoplasms - drug therapy; Mouth Neoplasms - metabolism; mRNA; Neoplasm Recurrence, Local; Oral cancer; Oral carcinoma; Oral squamous cell carcinoma; Pyrimidines - administration & dosage; Pyrimidines - pharmacology; Random Allocation; Rats; SOXB1 Transcription Factors - antagonists & inhibitors; Squamous cell carcinoma; Squamous Cell Carcinoma of Head and Neck - drug therapy; Squamous Cell Carcinoma of Head and Neck - metabolism; Stem cell transplantation; Stem cells; Synergistic effect; Tumors; Xenograft Model Antitumor Assays; United States > US; China; 4SC-202; Cancer stem cells (CSCs); Oral cancer; INK128
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2019.04.010

Treatment of oral squamous cell carcinoma (OSCC) remains a challenge because of the lack of effective early treatment strategies and high incidence of relapse. Here, we showed that combined 4SC-202 (a novel selective class I HDAC inhibitor) and INK128 (a selective mTORC1/C2 inhibitor) treatment exhibited synergistic effects on inhibiting cell growth, sphere-forming ability, subcutaneous tumor formation and ALDH1+ cancer stem cells (CSCs) in OSCC. The initiation of OSCC was significantly inhibited by combined treatment in 4NQO-induced rat model. In addition, upregulated SOX2 was associated with advanced and metastatic tumors in OSCC patients and was responsible for the drug-resistance property of OSCC cells. The inhibitory effect of combined treatment on cell viability and ALDH1+ CSCs were attenuated by SOX2 verexpression. Furthermore, combined treatment can effectively overcome chemoresistance and inhibit the growth of recurrent OSCC in vitro and in vivo. Mechanistically, 4SC-202 and INK128 repressed SOX2 expression through miR-429/miR-1181-mediated mRNA degradation and preventing cap-dependent mRNA translation, respectively. These results suggest that combined class I histone deacetylase and mTORC1/C2 inhibition suppresses the carcinogenesis and recurrence of OSCC by repressing SOX2.
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•Combined 4SC-202 (a novel selective class I histone deacetylases inhibitor) and INK128 (a selective mTORC1/C2 inhibitor) treatment exhibits synergistic effects on inhibiting cell growth and reducing ALDH1+ cancer stem cells in OSCC in vitro and in vivo.•Combined treatment significantly inhibits the initiation and recurrence of OSCC in rat models induced by 4NQO.•4SC-202 represses SOX2 expression through miR-429/miR-1181-mediated translational repression, while INK128 inhibits SOX2 via preventing cap-dependent mRNA translation.