Scavenging of Labile Heme by Hemopexin Is a Key Checkpoint in Cancer Growth and Metastases

Abstract

SUMMARY Hemopexin (Hx) is a scavenger of labile heme. Herein, we present data defining the role of tumor stroma-expressed Hx in suppressing cancer progression. Labile heme and Hx levels are inversely correlated in the plasma of patients with prostate cancer (PCa). Further, low expression of Hx in PCa biopsies characterizes poorly differentiated tumors and correlates with earlier time to relapse. Significantly, heme promotes tumor growth and metastases in an orthotopic murine model of PCa, with the most aggressive phenotype detected in mice lacking Hx. Mechanistically, labile heme accumulates in the nucleus and modulates specific gene expression via interacting with guanine quadruplex (G4) DNA structures to promote PCa growth. We identify c-MYC as a heme:G4-regulated gene and a major player in heme-driven cancer progression. Collectively, these results reveal that sequestration of labile heme by Hx may block heme-driven tumor growth and metastases, suggesting a potential strategy to prevent and/or arrest cancer dissemination.

Proximity Ligation Assay Detection of Protein–DNA Interactions—Is There a Link between Heme Oxygenase-1 and G-quadruplexes?

“…This expression is significantly reduced in Hmox1 −/− HSCs, which may result in the decreased uptake of heme. Recently, Canesin et al described heme-overload-induced changes in expressions of cell-cycle regulating genes [ 11 ]. We checked that these changes are not reflected by the gene expression profile in Hmox1 −/− HSCs ([ 42 ], data not shown), suggesting that Hmox1 −/− HSCs do not have significantly elevated free heme.…”

“…Thus, they could provide an additional element in the regulation of various biological functions. Very recently, the importance of G-quadruplexes in the promoter sequence for regulating the expression of c-Myc in prostate cancer cells has been directly demonstrated [ 11 ].…”

“…Rather less attention has been paid to the consequences of controlling free heme itself. A recent report highlighted the role of the stabilization of G4 by heme in the regulation of gene expression, including genes involved in cell-cycle progression [ 11 ]. However, there are still no data on the effect of the heme-induced and heme-degrading HMOX1 on G4 accumulation in cells.…”

Iron: An Essential Element of Cancer Metabolism

“…Similarly, ferritin (FT) decrease can result from activation of MYC, IRP2, or p53 mutation [51,155,185]. Such a vicious cycle is sustained as increased LIP promotes CDK, JAK/STAT, PI3K, MAPK/ERK pathways [172], whereas heme can further enhance ERK and MYC and inhibits p53 [181,186,187]. Lipocalin 2 (LCN2 or NGAL) is a soluble iron-binding glycoprotein expressed mainly by neutrophils [188].…”

“…In leukemia and lung cancer cells, increased heme synthesis and availability also increased cell proliferation by enhancing mitochondrial oxidative metabolism [214][215][216]. Furthermore, recent studies have demonstrated that labile heme fosters cell proliferation by inhibiting p53 [187] and inducing MYC [186]. Interestingly, heme was shown to interfere directly with the p53 gene in vitro and in vivo while inducing proteosomal degradation of p53 protein [187].…”