HDAC11 activity contributes to MEK inhibitor escape in uveal melanoma

Sathya Neelature Sriramareddy, Fernanda Faião-Flores, Michael F. Emmons, Biswarup Saha, Srikumar Chellappan, Clayton Wyatt, Inna Smalley, Jonathan D. Licht, Michael A. Durante, J. William Harbour, Keiran S.M. Smalley

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


We previously demonstrated that pan-HDAC inhibitors could limit escape from MEK inhibitor (MEKi) therapy in uveal melanoma (UM) through suppression of AKT and YAP/TAZ signaling. Here, we focused on the role of specific HDACs in therapy adaptation. Class 2 UM displayed higher expression of HDACs 1, 2, and 3 than Class 1, whereas HDACs 6, 8, and 11 were uniformly expressed. Treatment of UM cells with MEKi led to modulation of multiple HDACs, with the strongest increases observed in HDAC11. RNA-seq analysis showed MEKi to decrease the expression of multiple HDAC11 target genes. Silencing of HDAC11 significantly reduced protein deacetylation, enhanced the apoptotic response to MEKi and reduced growth in long-term colony formation assays across multiple UM cell lines. Knockdown of HDAC11 led to decreased expression of TAZ in some UM cell lines, accompanied by decreased YAP/TAZ transcriptional activity and reduced expression of multiple YAP/TAZ target genes. Further studies showed this decrease in TAZ expression to be associated with increased LKB1 activation and modulation of glycolysis. In an in vivo model of uveal melanoma, silencing of HDAC11 limited the escape to MEKi therapy, an effect associated with reduced levels of Ki67 staining and increased cleaved caspase-3. We have demonstrated a novel role for adaptive HDAC11 activity in UM cells, that in some cases modulates YAP/TAZ signaling leading to MEKi escape.

Original languageEnglish (US)
Pages (from-to)1840-1846
Number of pages7
JournalCancer Gene Therapy
Issue number12
StatePublished - Dec 2022
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Cancer Research


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