The role of myoglobin in epithelial cancers: Insights from transcriptomics

Abstract

The muscle-associated respiratory protein myoglobin (MB) is expressed in multiple types of cancer, including breast and prostate tumors. In Kaplan-Meier analyses of the two tumor types, MB positivity is associated with favorable prognoses. despite its well-characterized function in myocytes, the role of MB in cancer remains unclear. To study the impact of endogenous MB expression, small interfering RNA MB-knockdown cells were engineered using breast, prostate and colon cancer cell lines (MdA-MB468, LNcaP, dLd-1), and their transcriptomes were investigated using RNA-Seq at different oxygen levels. In MB-positive cells, increased expression of glycolytic genes was observed, which was possibly mediated by a higher activity of hypoxia-inducible factor 1α. In addition, the results of the gene set enrichment analysis suggested that MB contributed to fatty acid transport and turnover. MB-positive, wild-type-p53 LNcaP cells also exhibited increased expression of p53 target genes involved in cell cycle checkpoint control and prevention of cell migration. MB-positive cells expressing mutant p53 exhibited upregulation of genes associated with prolonged cancer cell viability and motility. Therefore, it was hypothesized that these transcriptomic differences may result from MB-mediated generation of nitric oxide or reactive oxygen species, thus employing established enzymatic activities of the globin. In summary, the transcriptome comparisons identified potential molecular functions of MB in carcinogenesis by highlighting the interaction of MB with key metabolic and regulatory processes.

Targeted Myoglobin Delivery as a Strategy for Enhancing the Sensitivity of Hypoxic Cancer Cells to Radiation

“…The monomeric heme protein myoglobin is expressed predominantly in skeletal and cardiac muscles where it was believed to function solely as an oxygen reservoir, binding O 2 under aerobic conditions iScience Article and releasing it to mitochondria for cellular respiration under hypoxia (Galluzzo et al, 2009;Ordway and Garry, 2004). In recent years, the ectopic expression of myoglobin in non-muscle tissues as well as cancer cell lines and tumors has been reported (Bicker et al, 2020;Flonta et al, 2009;Kristiansen et al, 2011;Meller et al, 2016). Expression profiling of tumors from patients with head and neck squamous cell carcinoma has revealed that myoglobin expression is associated with better prognosis (Meller et al, 2016).…”

Lessons from the post-genomic era: Globin diversity beyond oxygen binding and transport

“…HIF-1α is instead found to be regulating Mb mRNA expression levels by binding to a remote enhancer element located ~2.7 kb upstream of the Mb gene, upon experimental hypoxia [ 190 , 191 ]. Hypoxia-induced Mb expression regulation was reported in breast, prostate and colon cancer cells [ 196 ]. These data suggest that the hypoxic tumor microenvironment contributes to the upregulation of Mb in cancer cells.…”

“…This includes phosphorylation of p53, which regulates its downstream target genes, resulting in cell cycle arrest and apoptosis. Furthermore, oxidative stress also inactivates PHD2 which subsequently safeguards intact HIF-α, leading to downstream shifting in metabolic activities in a cell-specific manner [ 196 ]. In these processes, Mb-dependent oxygen binding and oxidative stress generation are crucial, while any free radical scavenging activity can potentially impede the process [ 200 ].…”

Myoglobin Protects Breast Cancer Cells Due to Its ROS and NO Scavenging Properties

“…By using an unbiased transcriptomics approach in combination with a siRNA-induced knockdown of MB and hypoxic versus normoxic incubation, a follow-up study reported an influence of MB on key metabolic and regulatory processes in these cancer cell lines. The RNA-Seq data suggested a functional impact of MB on ROS and NO homeostasis, correlating MB positively with increased HIF-1α and p53 signaling ( 31 ).…”