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, Fe²⁺, 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.

中文翻译：

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血红素加氧酶促进 B-Raf 依赖性黑素圈的形成。

血红素是一种被多种代谢过程利用的铁结合原卟啉分子，其生物合成和降解受到严格调控。两种密切相关的酶，血红素加氧酶 1 (HMOX1) 和血红素加氧酶 2 (HMOX2)，降解游离血红素以产生一氧化碳、Fe ²⁺和胆绿素。HMOX1 的表达受转录激活因子 NFE2L2 和转录抑制因子 Bach1 的控制。HMOX1 的转录和其他 NFE2L2 依赖性基因响应亲电子和活性氧物种而增加。许多肿瘤衍生细胞系的 NFE2L2 水平升高。NFE2L2 依赖基因的表达升高有助于肿瘤生长和对治疗的获得性耐药。在这里，我们报告了血红素加氧酶活性在人类黑色素瘤衍生细胞系形成的黑色素球中的新作用。通过Bach1 的去抑制或HMOX2的转录激活由致癌 B-Raf ^V600E转录诱导HMOX1导致黑素球形成增加。HMOX1 的基因消融减少黑色素层的形成。此外，用锡原卟啉抑制血红素加氧酶活性显着减少了由 Bach1 去抑制或 B-Raf ^V600E表达驱动的黑素球形成。全球转录组分析表明黑色素圈形成中涉及粘着斑和细胞外基质相互作用的基因。