Pharmacologic suppression of MITF expression via HDAC inhibitors in the melanocyte lineage

Satoru Yokoyama, Erez Feige, Laura L. Poling, Carmit Levy, Hans R. Widlund, Mehdi Khaled, Andrew L. Kung, David E. Fisher

Research output: Contribution to journalArticlepeer-review

Abstract

Melanoma incidence continues to rise at an alarming rate while effective systemic therapies remain very limited. Microphthalmia-associated transcription factor (MITF) is required for development of melanocytes and is an amplified oncogene in a fraction of human melanomas. Microphthalmia-associated transcription factor also plays an oncogenic role in human clear cell sarcomas, which typically exhibit melanoma-like features. Although pharmacologic suppression of MITF is of potential interest in a variety of clinical settings, it is not known to contain intrinsic catalytic activity capable of direct small molecule inhibition. An alternative drug-targeting strategy is to identify and interfere with lineage-restricted mechanisms required for its expression. Here, we report that multiple histone deacetylase (HDAC)-inhibitor drugs potently suppress MITF expression in melanocytes, melanoma and clear cell sarcoma cells. Although HDAC inhibitors may affect numerous cellular targets, we observed suppression of skin pigmentation by topical drug application as well as evidence of anti-melanoma efficacy in vitro and in mouse xenografts. Consequently, HDAC inhibitor drugs are candidates to play therapeutic roles in targeting conditions affecting the melanocyte lineage.

Original languageEnglish
Pages (from-to)457-463
Number of pages7
JournalPigment Cell and Melanoma Research
Volume21
Issue number4
DOIs
StatePublished - Aug 2008

Funding

FundersFunder number
National Institute of Arthritis and Musculoskeletal and Skin DiseasesR01AR043369

    Keywords

    • Clear cell sarcoma
    • HDAC inhibitor
    • MITF
    • Melanoma
    • Pigmentation

    Fingerprint

    Dive into the research topics of 'Pharmacologic suppression of MITF expression via HDAC inhibitors in the melanocyte lineage'. Together they form a unique fingerprint.

    Cite this