MYC directs transcription of MCL1 and eIF4E genes to control sensitivity of gastric cancer cells toward HDAC inhibitors

Wajana L. Labisso, Matthias Wirth, Natasa Stojanovic, Roland H. Stauber, Angelika Schnieke, Roland M. Schmid, Oliver H. Krämer, Dieter Saur, Günter Schneider

Research output: Contribution to journalArticlepeer-review

49 Scopus citations

Abstract

Histone deacetylases (HDACs) control fundamental physiological processes such as proliferation and differentiation. HDAC inhibitors (HDACi) induce cell cycle arrest and apoptosis of tumor cells. Therefore, they represent promising cancer therapeutics that appear particularly useful in combination therapies. Although HDACi are tested in current clinical trials, the molecular mechanisms modulating the cellular responses toward HDACi are incompletely understood. To gain insight into pathways that limit HDACi efficacy in gastric cancer, we treated a panel of gastric cancer cells with the clinically relevant HDACi suberoylanilide hydroxamic acid (SAHA). We report that higher expression levels of the anti-apoptotic BCL2 family members MCL1 and BCLXL were detectable in cells with high inhibitory concentration 50 (IC50) values for SAHA. Using RNAi, we show that MCL1 and BCLXL lower the efficacy of SAHA. To find strategies to interfere with MCL1 and BCLXL expression, we investigated molecular regulation of both proteins. We show that specific siRNAs against c-MYC as well as pharmacological inhibition of this cancer-relevant transcription factor reduced MCL1 and BCLXL expression. Subsequently, we observed an increase in SAHA efficacy. Our data furthermore demonstrate that two different molecular mechanisms are responsible for the modulation of these factors. Whereas c-MYC controls transcription of MCL1 directly, regulation of BCLXL was due to c-MYC's capability to regulate the eIF4E gene, which encodes a rate-limiting factor of eukaryotic translation. Our data reveal a new molecular mechanism for how c-MYC controls cell autonomous apoptosis and provide a rationale for a concerted inhibition of HDACs and c-MYC in gastric cancer.

Original languageEnglish
Pages (from-to)1593-1602
Number of pages10
JournalCell Cycle
Volume11
Issue number8
DOIs
StatePublished - 15 Apr 2012

Keywords

  • Apoptosis
  • Gastric cancer
  • HDAC
  • MCL1
  • c-MYC
  • eIF4E

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