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Heme oxygenase promotes B‐Raf‐dependent melanosphere formation
Author(s) -
Jasmer Kimberly J.,
Hou Jie,
Mannino Philip,
Cheng Jianlin,
Hannink Mark
Publication year - 2020
Publication title -
pigment cell and melanoma research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.618
H-Index - 105
eISSN - 1755-148X
pISSN - 1755-1471
DOI - 10.1111/pcmr.12905
Subject(s) - heme oxygenase , chemistry , oxygenase , heme , microbiology and biotechnology , biochemistry , biology , enzyme
Biosynthesis and degradation of heme, an iron‐bound protoporphyrin molecule utilized by a wide variety of metabolic processes, are tightly regulated. Two closely related enzymes, heme oxygenase 1 (HMOX1) and heme oxygenase 2 (HMOX2), degrade free heme to produce carbon monoxide, Fe 2+ , and biliverdin. HMOX1 expression is controlled via the transcriptional activator, NFE2L2, and the transcriptional repressor, Bach1. Transcription of HMOX1 and other NFE2L2‐dependent genes is increased in response to electrophilic and reactive oxygen species. Many tumor‐derived cell lines have elevated levels of NFE2L2. Elevated expression of NFE2L2‐dependent genes contributes to tumor growth and acquired resistance to therapies. Here, we report a novel role for heme oxygenase activity in melanosphere formation by human melanoma‐derived cell lines. Transcriptional induction of HMOX1 through derepression of Bach1 or transcriptional activation of HMOX2 by oncogenic B‐Raf V600E results in increased melanosphere formation. Genetic ablation of HMOX1 diminishes melanosphere formation. Further, inhibition of heme oxygenase activity with tin protoporphyrin markedly reduces melanosphere formation driven by either Bach1 derepression or B‐Raf V600E expression. Global transcriptome analyses implicate genes involved in focal adhesion and extracellular matrix interactions in melanosphere formation.