Scavenging of Labile Heme by Hemopexin is a Key Check-Point in Cancer Growth and Metastases

Abstract

Hemopexin (Hx) is a scavenger of labile heme, which is one of the most abundant molecules in our body. Here, we present data defining a novel role of Hx in suppressing cancer progression. By rigorously examining the levels of Hx and labile heme in two distinct cohorts, we demonstrated an inverse correlation between heme and Hx levels in the plasma of patients with prostate cancer. Further, low expression of Hx in prostate cancer biopsies characterizes poorly differentiated tumors and correlates with earlier time to relapse. By applying an orthotopic murine model of prostate cancer, we confirmed that heme treatment promotes tumor growth and frequency of metastases with the most aggressive phenotype of tumors implanted into 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 colony growth in anchorage-independent manner. We identified c-MYC as one of the heme: G4-regulated genes and a major player in heme-driven cancer hallmarks. Collectively, these results reveal a novel function of Hx in blocking heme-driven tumor growth and metastases. Sequestration of labile heme by Hx in the tumor microenvironment suggests a novel strategy to prevent and/or arrest cancer dissemination.