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HDAC11 activity contributes to MEK inhibitor escape in uveal melanoma

Cancer Gene Therapy volume 29, pages 1840–1846 (2022)Cite this article

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Abstract

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.

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Fig. 1: Treatment with a MEK inhibitor increases HDAC11 expression.
Fig. 2: Silencing of HDAC11 increases sensitivity to MEK inhibition.
Fig. 3: HDAC11 drives MEK inhibitor resistance in UM through upregulation of YAP/TAZ signaling.
Fig. 4: Silencing of HDAC11 limits escape from MEKi therapy in uveal melanoma mouse models.

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Acknowledgements

This work was supported by NCI/NIH R01 CA256193 to KSMS, JDL, and JWH.

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Authors and Affiliations

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

    Sathya Neelature Sriramareddy, Fernanda Faião-Flores, Michael F. Emmons, Biswarup Saha, Srikumar Chellappan & Keiran S. M. Smalley

  2. Department of Cancer Physiology, The Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, USA

    Clayton Wyatt & Inna Smalley

  3. University of Florida Health Sciences Center, Gainesville, FL, USA

    Jonathan D. Licht

  4. Sylvester Cancer Center, University of Miami, Miami, FL, USA

    Michael A. Durante & J. William Harbour

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Contributions

SNS, FF-F, MFE, BS, CW performed the experiments. SNS, MFE, SC, JDL, IS, MAD, JWH, and KSMS analyzed the data. SNS, MFE, IS, and KSMS wrote the manuscript. MAD, JWH, JDL, and KSMS edited the manuscript. All authors read and approved the final manuscript.

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Correspondence to Keiran S. M. Smalley.

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Sriramareddy, S.N., Faião-Flores, F., Emmons, M.F. et al. HDAC11 activity contributes to MEK inhibitor escape in uveal melanoma. Cancer Gene Ther 29, 1840–1846 (2022). https://doi.org/10.1038/s41417-022-00452-7

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