HO-1 and Heme: G-Quadruplex Interaction Choreograph DNA Damage Responses and Cancer Growth.

Giacomo Canesin,Barbara Wegiel,Anindhita Meena Muralidharan,Kenneth D Swanson

doi:10.3390/cells10071801

Giacomo Canesin, Barbara Wegiel + Show 2 more

Open Access

https://doi.org/10.3390/cells10071801

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Abstract

Many anti-cancer therapeutics lead to the release of danger associated pattern molecules (DAMPs) as the result of killing large numbers of both normal and transformed cells as well as lysis of red blood cells (RBC) (hemolysis). Labile heme originating from hemolysis acts as a DAMP while its breakdown products exert varying immunomodulatory effects. Labile heme is scavenged by hemopexin (Hx) and processed by heme oxygenase-1 (HO-1, Hmox1), resulting in its removal and the generation of biliverdin/bilirubin, carbon monoxide (CO) and iron. We recently demonstrated that labile heme accumulates in cancer cell nuclei in the tumor parenchyma of Hx knockout mice and contributes to the malignant phenotype of prostate cancer (PCa) cells and increased metastases. Additionally, this work identified Hx as a tumor suppressor gene. Direct interaction of heme with DNA G-quadruplexes (G4) leads to altered gene expression in cancer cells that regulate transcription, recombination and replication. Here, we provide new data supporting the nuclear role of HO-1 and heme in modulating DNA damage response, G4 stability and cancer growth. Finally, we discuss an alternative role of labile heme as a nuclear danger signal (NDS) that regulates gene expression and nuclear HO-1 regulated DNA damage responses stimulated by its interaction with G4.

Highlights

We demonstrated increased DNA damage marked by γH2AX foci in cells treated with heme and its colocalization with HO-1 staining in the nucleus
Is labile heme detected in the nucleus, but nuclear HO-1 is readily detected in many types of cancer cells within tumors
Our data indicate that heme promotes the accumulation of nuclear HO-1 as previously reported [53] and further that nuclear truncated HO-1 (tHO-1) increases prostate cancer colony growth in soft agar (Figure 5)

Summary

Introduction

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Panigrahy et al has demonstrated that tumor cells killed in the tumor stroma clearly promote cancer progression [10] This might be in part due to by chemotherapy or targeted therapy (“tumor cell debris”) stimulate cancer growth in a immune imbalance, but primarily due to altered gene expression in response to heme:G4 model of tumor dormancy [18]. Our published data indicate that labile heme or lack of Hx interaction within the promoter regions of key oncogenes including c-MYC [19] as well as in the tumor stroma clearly promote cancer progression [10]. This might be in part due to heme-induced HO-1 expression. These data suggest a mechanism via which HO1/heme shape gene expression and downstream signaling during carcinogenesis

Role of Heme Metabolism and Nuclear HO-1 in Gene Expression Control

Nuclear the C-terminal

Heme and G4 Interaction

Heme:G4 as Therapeutic Targets in Cancer

Findings

Discussion and Future Directions