Novel small molecular inhibitor of Pit-Oct-Unc transcription factor 1 suppresses hepatocellular carcinoma cell proliferation

Life Sci. 2021 Jul 15:277:119521. doi: 10.1016/j.lfs.2021.119521. Epub 2021 May 1.

Abstract

Hepatocellular carcinoma (HCC) is one of the most prevalent fatal malignancies in the Chinese population, due to high rates of hepatitis virus infection. Molecular targeted drugs such as sorafenib are the anti-tumor agents of choice for HCC treatment, but their results are generally unsatisfactory. In the present study the use of Pit-Oct-Unc transcription factor 1 (OCT1/POU2F1) as a potential therapeutic target for HCC was investigated, and a novel small molecular inhibitor of OCT1 (SMIO-1) was designed and its therapeutic efficacy against HCC was assessed. OCT1 expression was higher in HCC specimens than in corresponding non-tumor tissues, and higher OCT1 was associated with poorer prognosis in advanced HCC patients undergoing sorafenib treatment. For the first time, the novel SMIO-1 was investigated in conjunction with OCT1 via molecular docking. Interaction between SMIO-1 and OCT1 was confirmed via OCT1 point mutation. Treatment with SMIO-1 repressed OCT1 transcription factor activation by disrupting the interaction between OCT1 and its cofactors. It also repressed the proliferation and metastasis of HCC cells, and inhibited proliferation-related and metastasis-related genes downstream of OCT1. Therefore, SMIO-1 is a promising strategy for HCC treatment.

Keywords: Hepatocellular carcinoma; Pit-Oct-Unc transcription factor 1; Proliferation and metastasis; Protein interaction; Small molecular inhibitor of OCT1.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / metabolism*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • China
  • HEK293 Cells
  • Humans
  • Liver Neoplasms / genetics
  • Liver Neoplasms / metabolism
  • Male
  • Mice
  • Mice, Nude
  • Molecular Docking Simulation
  • Octamer Transcription Factor-1 / antagonists & inhibitors
  • Octamer Transcription Factor-1 / genetics*
  • Octamer Transcription Factor-1 / metabolism*
  • Prognosis
  • Sorafenib / pharmacology
  • Transcription Factor Pit-1 / pharmacology

Substances

  • Antineoplastic Agents
  • Octamer Transcription Factor-1
  • POU2F1 protein, human
  • Transcription Factor Pit-1
  • Sorafenib