The epigenetic regulation of Dicer and microRNA biogenesis by Panobinostat
Nicholas C Hoffend1, William J Magner1,2, Thomas B Tomasi1,2,3
1a Laboratory of Molecular Medicine, Department of Immunology , Roswell Park Cancer Institute , Buffalo , NY , USA.
Abstract:
microRNAs (miRs) are small noncoding RNAs that regulate/fine tune many cellular protein networks by targeting mRNAs for either degradation or translational inhibition. Dicer, a type III endoribonuclease, is a critical component in miR biogenesis and is required for mature microRNA production. Abnormal Dicer expression occurs in numerous cancer types and correlates with poor patient prognosis. Recent reports have demonstrated that epigenetic agents, including histone deacetylase inhibitors (HDACi), may regulate Dicer and miR expression. HDACi are a class of epigenetic agents used to treat cancer, viral infections, and inflammatory disorders. However, little is known regarding the epigenetic regulation of miR biogenesis and function. We therefore investigated whether clinically successful HDACi modulated Dicer expression and found that Panobinostat, a clinically approved HDACi, enhanced Dicer expression via posttranscriptional mechanisms. Studies using proteasome inhibitors suggested that Panobinostat regulated the proteasomal degradation of Dicer. Further studies demonstrated that Panobinostat, despite increasing Dicer protein expression, decreased Dicer activity. This suggests that Dicer protein levels do not necessarily correlate with Dicer activity and mature miR levels. Taken together, we present evidence here that Panobinostat posttranscriptionally regulates Dicer/miR biogenesis and suggest Dicer as a potential therapeutic target in cancer.
Insights
Histone deacetylase inhibitors like Panobinostat affect microRNA (miR) production by altering Dicer protein levels and activity. This study reveals Panobinostat
Area of Science:
- Molecular Biology
- Epigenetics
- Cancer Research
Background:
- MicroRNAs (miRs) are key regulators of cellular processes, with Dicer being essential for their biogenesis.
- Aberrant Dicer expression is linked to cancer progression and poor prognosis.
- Histone deacetylase inhibitors (HDACi) are emerging epigenetic agents with therapeutic potential.
Purpose of the Study:
- To investigate the effect of clinically relevant HDAC inhibitors on Dicer expression and microRNA biogenesis.
- To elucidate the mechanisms underlying HDACi-mediated regulation of Dicer.
- To assess the therapeutic potential of targeting Dicer in cancer.
Main Methods:
- Treatment of cells with Panobinostat, a clinically approved HDAC inhibitor.
- Assessment of Dicer protein expression and activity.
- Investigation of proteasomal degradation pathways using proteasome inhibitors.
- Analysis of mature microRNA levels.
Main Results:
- Panobinostat significantly enhanced Dicer protein expression through posttranscriptional mechanisms.
- Evidence suggests Panobinostat promotes Dicer proteasomal degradation.
- Despite increased Dicer protein, Panobinostat reduced Dicer activity and subsequent mature miR levels.
- Dicer protein levels do not directly correlate with its enzymatic activity or mature miR output.
Conclusions:
- Panobinostat posttranscriptionally regulates Dicer and microRNA biogenesis.
- Dicer activity, not just protein level, is crucial for miR production.
- Dicer represents a potential therapeutic target in cancer, modulated by epigenetic agents.
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