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

Cancer Lett. 2019 Jul 10:454:108-119. doi: 10.1016/j.canlet.2019.04.010. Epub 2019 Apr 11.

Abstract

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.

Keywords: 4SC-202; Cancer stem cells (CSCs); INK128; Oral cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Benzamides / administration & dosage
  • Benzamides / pharmacology
  • Benzoxazoles / administration & dosage
  • Benzoxazoles / pharmacology
  • Carcinogenesis
  • Drug Synergism
  • Female
  • Histone Deacetylase 1 / antagonists & inhibitors*
  • Humans
  • 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
  • Mice
  • Mice, Inbred BALB C
  • Mouth Neoplasms / drug therapy*
  • Mouth Neoplasms / metabolism
  • Neoplasm Recurrence, Local
  • Pyrimidines / administration & dosage
  • Pyrimidines / pharmacology
  • Random Allocation
  • Rats
  • SOXB1 Transcription Factors / antagonists & inhibitors*
  • Squamous Cell Carcinoma of Head and Neck / drug therapy*
  • Squamous Cell Carcinoma of Head and Neck / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • Benzamides
  • Benzoxazoles
  • Pyrimidines
  • SOXB1 Transcription Factors
  • domatinostat
  • Mechanistic Target of Rapamycin Complex 1
  • Mechanistic Target of Rapamycin Complex 2
  • Histone Deacetylase 1
  • sapanisertib