Abstract
Heme oxygenases (HOs) act on heme degradation to produce carbon monoxide (CO), free iron, ferritin, and biliverdin. Upregulation of cellular HO-1 levels is signature of oxidative stress for its downstream effects particularly under pro-oxidative status. Subcellular traffics of HO-1 to different organelles constitute a network of interactions compromising a variety of effectors such as pro-oxidants, ROS, mitochondrial enzymes, and nucleic transcription factors. Some of the compartmentalized HO-1 have been demonstrated as functioning in the progression of cancer. Emerging data show the multiple roles of HO-1 in tumorigenesis from pathogenesis to the progression to malignancy, metastasis, and even resistance to therapy. However, the role of HO-1 in tumorigenesis has not been systematically addressed. This review describes the crosstalk between HO-1 and oxidative stress, and following redox regulation in the tumorigenesis. HO-1-regulated signaling pathways are also summarized. This review aims to integrate basic information and current progress of HO-1 in cancer research in order to enhance the understandings and facilitate following studies.
Highlights
Oxidative stress is referred as a pro-oxidative circumstance, occurring at the imbalance between oxidants and antioxidants in favor of the oxidants, which has been implicated in governing normal physiological activities and pathological processes
In addition to heme metabolism, heme oxygenase (HO)-1 is induced by a broad range of incitements including oxidants, cytokines, growth factors and hormones, heavy metals, and physical cues, especially being highly sensitive to pro-oxidant stimuli, such as ultraviolet, heavy metals, inflammatory cytokines, and iron-containing molecules, that contribute to a regulatory network of cell functions [8]
HO-1 lacking the Cterminal transmembrane segment is susceptible to acetylation by p300 and CREB-binding protein histone acetyltransferase (CREBBP) in the nucleus, which is essential for the nuclear translocation of HO-1 to enhance tumor growth and invasiveness [57]
Summary
Bilirubin possesses a potent antioxidant and a quick oxidation by H2O2 back to biliverdin, forming a catalytic antioxidant cycle driven by NADPH and biliverdin reductase [36]. Several transcription factors are found to bind to the promoter regions of HMOX1 and participate in its transcriptional activity. Several signaling pathways upstream of the activation of transcription factors have been identified to regulate HMOX1 expression including MAPK, PI3K/Akt, and protein kinases (PKA, PKC, and PKG) [42]. BACH1 is a basic leucine zipper transcription factor, forming a heterodimer with Maf family proteins to compete with the ARE site and prevent the access of Nrf for HMOX1 expression [46,47]. MiR217 and miR-377 work together to reduce the mRNA abundance of HO-1 and thereby result in a decrease of HO-1 proteins [49] Both miR-24 and miR-1225 upregulate HO-1 by activating the Nrf pathway [50,51]. HMOX1 expression is associated with gene polymorphism in the promoter regions in which shorter (GT) repeats in the HMOX1 promoter exhibit a higher transcriptional activity [55]
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