Expression of heme oxygenase‐1 in human leukemic cells and its regulation by transcriptional repressor Bach1

Abstract

Heme oxygenase (HO)-1 has anti-oxidative, anti-inflammatory, and anti-apoptotic activities. However, little is known about the regulation of HO-1 in human primary acute myeloid leukemia (AML) cells. Here we investigated the expression of HO-1 in primary and established AML cells as well as other types of leukemic cells and normal monocytes, and its regulatory mechanism by the transcriptional repressor, BTB and CNC homology 1 (Bach1), and the activator, nuclear factor erythroid-derived 2 related factor 2 (Nrf2). Leukemic cell lines such as U937 expressed little HO-1, whereas most freshly isolated AML cells and monocytes expressed substantial amounts of HO-1, along with Bach1 and Nrf2. When U937 cells were treated with phorbol myristate acetate (PHA) or c-interferon, they significantly expressed both HO-1 and Bach1, like primary AML cells. Treatment with lipopolysaccharide (LPS) enhanced HO-1 expression in U937 cells but suppressed it in primary monocytes and PMA-treated U937 cells. In HO-1-expressing cells, Bach1 was localized in the cytoplasm, but Nrf2 was localized in the nuclei. Chromatin immunoprecipitation assay of these cells revealed the preferential binding of Nrf2 over Bach1 to Maf-recognition elements, the enhancer regions of the HO-1 gene. The downregulation of the HO-1 gene with siRNA increased a cytotoxic effect of an anticancer drug on primary AML cells, whereas the downregulation of Bach1 increased HO-1 expression, leading to enhanced survival. These and other results show that Bach1 plays a critical role in regulating HO-1 gene expression in AML cells and its expression suppresses their survival by downregulating HO-1 expression. Thus, functional upregulation of Bach1 is a potential strategy for antileukemic therapy. (Cancer Sci 2010; 101: 1409-1416 H eme oxygenase (HO)-1 is an inducible form of HO, which degrades heme into carbon monoxide, Fe 2+ , and biliverdin. HO-1 possesses cytoprotective properties such as antioxidative, anti-inflammatory, and anti-apoptotic functions, and these properties are beneficial to cells, tissues, organs, and organisms.(1,2) Accumulating evidence shows that induction of HO-1 is a promising strategy for the treatment of various ischemic and inflammatory diseases.(1-3) In addition, HO-1 is a potential target for cancer therapy because this enzyme gives survival and growth advantages to malignant cells by means of its anti-apoptotic activity.(4-8) Aberrant expression of HO-1 in human cancers, including hematological malignancies, is implicated in oncogenesis and chemoresistance. In primary CML cells and the CML-derived K562 cell line, constitutively expressed HO-1 has been identified as a BCR ⁄ ABL oncoprotein-dependent survival factor.(9) Other studies have shown that modulation of HO-1 expression affects cellular growth or survival of myeloid leukemia cells.(10-12) Therefore, understanding the regulatory system for the HO-1 expression in myeloid lineage cells seems to be critically important.HO-1 is induced in response to oxidative stress, and its expression is regul...

The BTB and CNC Homology 1 (BACH1) Target Genes Are Involved in the Oxidative Stress Response and in Control of the Cell Cycle

“…Overexpression of miR-155 has been observed in several types of B-cell lymphomas and induces B-cell malignancies in transgenic mice (73). Down-regulation of BACH1 in human acute myeloid leukemia cells decreases the cytotoxic effect of the anticancer drug cytosine arabinoside, rendering functional up-regulation of BACH1 a potential strategy for antileukemic therapy (11). In this respect, we have identified here two noncoding vault RNAs as BACH1 targets whose expression has been linked to Mitoxantrone resistance in human malignant cells (74).…”

“…Among other proteins involved in the heme degradation pathway, HMOX1 and the biliverdin reductases A and B were proposed as serum biomarkers for the early detection of Alzheimer disease (10). Furthermore, BACH1 expression was down-regulated by microRNAs in viral infection-associated cancerogenesis (11)(12)(13).…”

Signaling to heme oxygenase-1 and its anti-inflammatory therapeutic potential

“…In rodent macrophages, HO-1 has been shown to be up-regulated by lipopolysaccharide (LPS) [21][22][23], which then attenuates the expression of various proinflammatory genes including cyclooxygenase-2, inducible nitric oxide (NO) synthase (iNOS), tumor necrosis factor (TNF)- or interleukin (IL)-6 [18,24] (Figure 1). In contrast to the LPS-dependent induction of HO-1 in rodent macrophages, gene expression of HO-1 is down-regulated by treatment with LPS in human monocytes [25]. More recently, the myeloid cell-specific immunomodulatory functions of HO-1 have also been investigated in a conditional HO-1 knockout mouse model.…”

HO-1, RET and PML as possible markers for risk stratification of acute myelocytic leukemia and prognostic evaluation

“…In addition, HO-1 expression in CLL cells exceeds that in normal lymphocytes. In response to disease or stress, HO-1 expression results in resistance to cell apoptosis and promotes cell proliferation (26). Stuart et al (27) demonstrated that HO-1 was involved in the regulation of leukemia cell apoptosis, proliferation and differentiation through NF-κB, ROS and Nrf2.…”