Single-Cell Sequencing Identifies Master Regulators Affected by Panobinostat in Neuroblastoma Cells
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Giorgio Milazzo1, Giovanni Perini1, Federico M Giorgi1
1Department of Pharmacy and Biotechnology, University of Bologna, Via Selmi 3, 40126 Bologna, Italy.
Abstract:
The molecular mechanisms and gene regulatory networks sustaining cell proliferation in neuroblastoma (NBL) cells are still not fully understood. In this tumor context, it has been proposed that anti-proliferative drugs, such as the pan-HDAC inhibitor panobinostat, could be tested to mitigate tumor progression. Here, we set out to investigate the effects of panobinostat treatment at the unprecedented resolution offered by single-cell sequencing. We identified a global senescence signature paired with reduction in proliferation in treated Kelly cells and more isolated transcriptional responses compatible with early neuronal differentiation. Using master regulator analysis, we identified BAZ1A, HCFC1, MAZ, and ZNF146 as the transcriptional regulators most significantly repressed by panobinostat. Experimental silencing of these transcription factors (TFs) confirmed their role in sustaining NBL cell proliferation in vitro.
Insights
Panobinostat treatment induces senescence and reduces proliferation in neuroblastoma (NBL) cells. Key transcription factors (TFs) like BAZ1A, HCFC1, MAZ, and ZNF146 were identified as critical for NBL cell growth.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Neuroblastoma (NBL) cell proliferation mechanisms and gene regulatory networks remain incompletely understood.
- Pan-HDAC inhibitors like panobinostat are potential anti-proliferative agents for NBL treatment.
Purpose of the Study:
- To investigate the effects of panobinostat on NBL cells using single-cell sequencing.
- To identify key transcriptional regulators involved in NBL cell proliferation.
Main Methods:
- Single-cell RNA sequencing of panobinostat-treated NBL cells.
- Master regulator analysis to identify key transcription factors.
- Experimental validation of identified transcription factors via gene silencing.
Main Results:
- Panobinostat treatment induced a global senescence signature and reduced proliferation in Kelly NBL cells.
- Transcriptional changes suggested early neuronal differentiation.
- BAZ1A, HCFC1, MAZ, and ZNF146 were identified as significantly repressed by panobinostat.
- Silencing these TFs confirmed their role in NBL cell proliferation.
Conclusions:
- Panobinostat impacts NBL cell proliferation through senescence induction and repression of key TFs.
- BAZ1A, HCFC1, MAZ, and ZNF146 are crucial for maintaining NBL cell proliferation.
- These findings offer insights into NBL therapeutic strategies targeting gene regulation.
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