Division of Biological Sciences, University of Missouri, Columbia, Missouri, USA.
Christopher Bond Life Sciences Center, University of Missouri, Columbia, Missouri, USA.
Pigment Cell Melanoma Res. 2020 Nov;33(6):850-868. doi: 10.1111/pcmr.12905. Epub 2020 Jul 9.
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 , 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 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 expression. Global transcriptome analyses implicate genes involved in focal adhesion and extracellular matrix interactions in melanosphere formation.
血红素的生物合成和降解是一个受到严格调控的过程，血红素是一种铁结合的原卟啉分子，被广泛的代谢过程所利用。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），可以将游离血红素降解为一氧化碳、铁和胆绿素。HMOX1 的表达受转录激活因子 NFE2L2 和转录抑制因子 Bach1 控制。HMOX1 和其他 NFE2L2 依赖性基因的转录在受到亲电子和活性氧物种的刺激时会增加。许多肿瘤衍生的细胞系中 NFE2L2 的水平升高。NFE2L2 依赖性基因的高表达促进了肿瘤的生长和对治疗的获得性耐药。在这里，我们报道了血红素加氧酶活性在人黑色素瘤衍生细胞系中黑素小体形成中的一个新作用。通过 Bach1 的去抑制或致癌 B-Raf 的转录激活诱导 HMOX1 的转录诱导，导致黑素小体形成增加。HMOX1 的基因缺失会减少黑素小体的形成。此外，用锡原卟啉抑制血红素加氧酶活性，显著减少了由 Bach1 去抑制或 B-Raf 表达驱动的黑素小体形成。全基因组转录组分析表明，参与黏附斑和细胞外基质相互作用的基因参与了黑素小体的形成。
