HDAC2 deficiency sensitizes colon cancer cells to TNFα-induced apoptosis through inhibition of NF-κB activity

Pawan Kaler, Takehiko Sasazuki, Senji Shirasawa, Leonard H. Augenlicht, Lidija Klampfer

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

HDAC inhibitors exert potent anti-tumorigenic and anti-inflammatory activity. Their effects are selective for transformed cells, and we recently demonstrated that transformation of epithelial cells with k-Ras sensitizes cells to HDACi induced apoptosis. The aim of this study was to determine whether the ability of HDACi to modulate signaling by a major pro-inflammatory cytokine, TNFα, is also restricted to cells that harbor mutant k-Ras. We used the system of two isogenic cell lines that differ by the presence of mutant k-Ras, HCT116 and Hke3 cells. Treatment of cells with TNFα alone did not induce apoptosis; however HDACi potentiated TNFα-induced apoptosis in both HCT116 and Hke3 cells. Thus, the ability of HDACi to sensitize cells to TNFα-induced apoptosis appears to be k-Ras independent. We demonstrated that HDACi inhibited TNFα-induced NF-κB transcriptional and DNA binding activity in both cell lines, underlying the increased apoptosis in cells treated with both agents. We showed that overexpression of HDAC2 enhanced TNFα-induced NF-κB activity and that silencing of HDAC2 decreased NF-κB activity. Finally, silencing of HDAC2 expression was sufficient to sensitize colon cancer cells to TNFα-induced apoptosis. The ability of HDACi to interfere with NF-κB activity is likely to contribute to their potent anti-tumorigenic and anti-inflammatory activity.

Original languageEnglish (US)
Pages (from-to)1507-1518
Number of pages12
JournalExperimental Cell Research
Volume314
Issue number7
DOIs
StatePublished - Apr 15 2008

Fingerprint

Colonic Neoplasms
Apoptosis
HCT116 Cells
Anti-Inflammatory Agents
Cell Line
Histone Deacetylase Inhibitors
Epithelial Cells
Cytokines
DNA

Keywords

  • Apoptosis, Histone deacetylase 2
  • Histone deacetylase inhibitors
  • NF-κB
  • Tumor necrosis factor alpha

ASJC Scopus subject areas

  • Cell Biology

Cite this

HDAC2 deficiency sensitizes colon cancer cells to TNFα-induced apoptosis through inhibition of NF-κB activity. / Kaler, Pawan; Sasazuki, Takehiko; Shirasawa, Senji; Augenlicht, Leonard H.; Klampfer, Lidija.

In: Experimental Cell Research, Vol. 314, No. 7, 15.04.2008, p. 1507-1518.

Research output: Contribution to journalArticle

Kaler, Pawan ; Sasazuki, Takehiko ; Shirasawa, Senji ; Augenlicht, Leonard H. ; Klampfer, Lidija. / HDAC2 deficiency sensitizes colon cancer cells to TNFα-induced apoptosis through inhibition of NF-κB activity. In: Experimental Cell Research. 2008 ; Vol. 314, No. 7. pp. 1507-1518.
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