2. Academic Validation
  3. SUV39H1 regulates human colon carcinoma apoptosis and cell cycle to promote tumor growth

SUV39H1 regulates human colon carcinoma apoptosis and cell cycle to promote tumor growth

  • Cancer Lett. 2020 Apr 28:476:87-96. doi: 10.1016/j.canlet.2020.02.004.
Chunwan Lu 1,  John D Klement 2,  Dafeng Yang 2,  Thomas Albers 3,  Iryna O Lebedyeva 4,  Jennifer L Waller 5,  Kebin Liu 6
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA, 30912, USA; Georgia Cancer Center, Medical College of Georgia, Augusta, GA, 30912, USA; Charlie Norwood VA Medical Center, Augusta, GA, 30904, USA. Electronic address: Clu@augusta.edu.
  • 2 Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA, 30912, USA; Georgia Cancer Center, Medical College of Georgia, Augusta, GA, 30912, USA; Charlie Norwood VA Medical Center, Augusta, GA, 30904, USA.
  • 3 Georgia Cancer Center, Medical College of Georgia, Augusta, GA, 30912, USA.
  • 4 Department of Chemistry and Physics, Augusta University, Augusta, GA, 30904, USA.
  • 5 Department of Population Health Sciences, Augusta University, Augusta, GA, 30912, USA.
  • 6 Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA, 30912, USA; Georgia Cancer Center, Medical College of Georgia, Augusta, GA, 30912, USA; Charlie Norwood VA Medical Center, Augusta, GA, 30904, USA. Electronic address: Kliu@augusta.edu.
PMID: 32061753 DOI: 10.1016/j.canlet.2020.02.004
Abstract

Trimethylation of histone 3 lysine 9 (H3K9me3) at gene promoters is a major epigenetic mechanism that silences gene expression. We have developed a small molecule inhibitor for the H3K9me3-specific Histone Methyltransferase SUV39H1. We report here that FAS expression is significantly down-regulated and SUV39H1 expression is significantly up-regulated in human colorectal carcinoma (CRC) as compared to normal colon. SUV39H1-selective inhibitor F5446 decreased H3K9me3 deposition at the FAS promoter, increased Fas expression, and increased CRC cell sensitivity to FasL-induced Apoptosis in vitro. Furthermore, inhibition of SUV39H1 altered the expression of genes with known functions in DNA replication and cell cycle in the metastatic colon carcinoma cells, which is associated with cell cycle arrest at S phase in the metastatic human colon carcinoma cells, resulting in tumor cell Apoptosis and growth inhibition in a concentration-dependent manner in vitro. Moreover, F5446 increased 5-FU-resistant human CRC sensitivity to both 5-FU- and FasL-induced Apoptosis and inhibited tumor cell growth in vitro. More importantly, F5446 suppressed human colon tumor xenograft growth in vivo. Our data indicate that pharmacological inhibition of SUV39H1 is an effective approach to suppress human CRC.

Keywords

5-FU; Chemoresistance; Fas; H3K9me3; Metastasis; SUV39H1.

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