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

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

研究成果: ジャーナルへの寄稿学術誌査読

30 被引用数 (Scopus)

抄録

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.

本文言語英語
ページ(範囲)1507-1518
ページ数12
ジャーナルExperimental Cell Research
314
7
DOI
出版ステータス出版済み - 4月 15 2008
外部発表はい

!!!All Science Journal Classification (ASJC) codes

  • 細胞生物学

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