Abstract
Myoglobin (MB) is not only strongly expressed in myocytes, but also at much lower levels in different cancer entities. 40% of breast tumors are MB-positive, with the globin being co-expressed with markers of tumor hypoxia in a proportion of cases. In breast cancer, MB expression is associated with a positive hormone receptor status and patient prognosis. In prostate cancer, another hormone-dependent cancer type, 53% of tumors were recently shown to express MB. Especially in more aggressive prostate cancer specimen MB expression also correlates with increased patient survival rates. Both findings might be due to tumor-suppressing properties of MB in cancer cells. In contrast to muscle, MB transcription in breast and prostate cancer mainly depends on a novel, alternative promoter site. We show here that its associated transcripts can be upregulated by hypoxia and downregulated by estrogens and androgens in MCF7 breast and LNCaP prostate cancer cells, respectively. Bioinformatic data mining of epigenetic histone marks and experimental verification reveal a hitherto uncharacterized transcriptional network that drives the regulation of the MB gene in cancer cells. We identified candidate hormone-receptor binding elements that may interact with the cancer-associated MB promoter to decrease its activity in breast and prostate cancer cells. Additionally, a regulatory element, 250 kb downstream of the promoter, acts as a hypoxia-inducible site within the transcriptional machinery. Understanding the distinct regulation of MB in tumors will improve unraveling the respiratory protein’s function in the cancer context and may provide new starting points for developing therapeutic strategies.
Highlights
The respiratory protein myoglobin (MB) is expressed at high concentrations (~200–300 μM) in human skeletal and cardiac myocytes and, at much lower levels, in smooth muscle cells [1,2,3]
Mainly the alternative MB variants starting at upstream exon 5u were transcribed, while the MB transcript mainly expressed in myocytes was hardly detectable [18]
The architecture of the human MB gene has been revised by inclusion of several novel upstream exons, which produce alternatively spliced mRNAs originating at novel promoter regions [21]
Summary
The respiratory protein myoglobin (MB) is expressed at high concentrations (~200–300 μM) in human skeletal and cardiac myocytes and, at much lower levels, in smooth muscle cells [1,2,3]. At its prosthetic heme group, the protein is able to bind gaseous ligands, with its main task being the transport and storage of O2 in myocytes [2,4]. The Gene Regulatory Network of Myoglobin in Cancer diving mammals even revealed a direct correlation between myocytic Mb levels and O2 supply [5]. Deoxy-MB is instead able to produce NO, which in turn can inhibit mitochondrial O2 consumption and facilitate vasodilation in smooth muscle cells [11]
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