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Updated: Sep 29, 2025

Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
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HDAC11 activity contributes to MEK inhibitor escape in uveal melanoma

Sathya Neelature Sriramareddy1, Fernanda Faião-Flores1, Michael F Emmons1

  • 1The Department of Tumor Biology, The Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, USA.

Cancer Gene Therapy
|March 25, 2022
PubMed

Insights

Histone deacetylase 11 (HDAC11) promotes resistance to MEK inhibitor (MEKi) therapy in uveal melanoma (UM). Inhibiting HDAC11 enhances apoptosis and limits tumor growth, offering a new therapeutic strategy for UM.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Uveal melanoma (UM) often develops resistance to MEK inhibitor (MEKi) therapy.
  • Pan-histone deacetylase (HDAC) inhibitors can limit MEKi resistance by suppressing AKT and YAP/TAZ signaling.

Purpose of the Study:

  • To investigate the specific roles of individual HDACs in UM therapy adaptation.
  • To determine the involvement of HDAC11 in MEKi resistance in UM.

Main Methods:

  • Comparative analysis of HDAC expression in UM Class 1 and Class 2.
  • Treatment of UM cells with MEKi and assessment of HDAC modulation.
  • RNA-sequencing to identify HDAC11 target genes.
  • HDAC11 silencing and evaluation of its effects on protein deacetylation, apoptosis, and cell growth.
  • Analysis of YAP/TAZ signaling pathway and its target genes after HDAC11 knockdown.
  • In vivo studies using a UM xenograft model.

Main Results:

  • Class 2 UM showed higher expression of HDACs 1, 2, and 3 compared to Class 1.
  • MEKi treatment increased HDAC11 expression in UM cells.
  • Silencing HDAC11 reduced protein deacetylation, enhanced MEKi-induced apoptosis, and inhibited long-term colony formation.
  • HDAC11 knockdown decreased TAZ expression, YAP/TAZ transcriptional activity, and target gene expression in some UM cell lines.
  • HDAC11 silencing in vivo limited MEKi escape, evidenced by reduced Ki67 and increased cleaved caspase-3.

Conclusions:

  • Adaptive HDAC11 activity plays a critical role in UM cells' resistance to MEKi therapy.
  • HDAC11 modulates YAP/TAZ signaling, contributing to MEKi escape.
  • Targeting HDAC11 represents a potential therapeutic strategy to overcome MEKi resistance in UM.

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