Bach1 is critical for the transformation of mouse embryonic fibroblasts by RasV12 and maintains ERK signaling

Abstract

Reactive oxygen species (ROS), by-products of aerobic respiration, promote genetic instability and contribute to the malignant transformation of cells. Among the genes related to ROS metabolism, Bach1 is a repressor of the oxidative stress response, and a negative regulator of ROS-induced cellular senescence directed by p53 in higher eukaryotes. While ROS are intimately involved in carcinogenesis, it is not clear whether Bach1 is involved in this process. We found that senescent Bach1-deficient mouse embryonic fibroblasts (MEFs) underwent spontaneous immortalization the same as did the wild-type cells. When transduced with constitutively active Ras (H-Ras(V12)), the proliferation and colony formation of these cells in vitro were markedly reduced. When transplanted into athymic nude mice, the growth and vascularization of tumors derived from Bach1-deficient cells were also decreased. Gene expression profiling of the MEFs revealed a new H-Ras(V12) signature, which was distinct from the previously reported signatures in epithelial tumors, and was partly dependent on Bach1. The Bach1-deficient cells showed diminished phosphorylation of MEK and ERK1/2 in response to H-Ras(V12), which was consistent with the alterations in the gene expression profile, including phosphatase genes. Finally, Bach1-deficient mice were less susceptible to 4-nitroquinoline-1-oxidide (4-NQO)-induced tongue carcinoma than wild-type mice. Our data provide evidence for a critical role of Bach1 in cell transformation and tumor growth induced by activated H-Ras(V12).

Bach1Deficiency and Accompanying Overexpression of Heme Oxygenase-1 Do Not Influence Aging or Tumorigenesis in Mice

“…Interestingly, the genes expression signature of the Bach1 -deficient livers disappeared when examined at 100 weeks of age (Figure 3(a)). The 530 gene sets showed overlap with previously published Bach1 knockout signature in MEFs (25 gene entities, Figure 3(b)) [39]. To our surprise, hierarchical clustering of the 25 entities common for both signatures demonstrated that all genes except for Hmox1 returned to the normal levels similar to those in wild-type livers (Figure 3(c)).…”

“…Also Bach1 -deficient mice are less susceptible to 4-nitroquinoline-1-oxide- (4-NQO-) induced tongue carcinoma than wild-type mice [39]. These observations suggest that higher HO-1 levels may be causal for the tumor-suppressive phenotype of Bach1 deficiency in this experimental model.…”

“…The p53-Bach1 interaction is inhibited by the tumor suppressor p19 ARF [38], which is consistent with the senescence-restricting function of Bach1. Furthermore, Bach1 -deficient MEFs are resistant to transformation by activated H-Ras oncogene, which is known to utilize increased levels of ROS for transformation [39]. Therefore, a reduction in the Bach1 activity may lead to an enhancement in the tumor-resistant phenotype.…”

Wearing Red for Signaling: The Heme-Bach Axis in Heme Metabolism, Oxidative Stress Response and Iron Immunology

“…Consistent with this idea, Bach1-deficient MEFs are resistant to transformation by the H-Ras V12 oncogene and less susceptible to 4-nitroquinoline-1-oxidide (4-NQO)-induced tongue carcinoma than wild-type mice (Nakanome et al 2013). These results suggest that the development of some cancers depends on Bach1 to modulate the gene expression pattern in a favorable way for transformation.…”

ΔNp63 targets cytoglobin to inhibit oxidative stress-induced apoptosis in keratinocytes and lung cancer

“…47 One widely accepted hypothesis proposes that the accumulation of oxidative damage arising from endogenously produced ROS leads to cellular senescence, tissue degeneration and age-related disorders. [48][49][50][51][52][53][54][55][56][57][58][59][60][61][62] In contrast, ΔNp63 has a crucial role in maintaining the proliferative potential of epithelial cells and counteracting cellular senescence and organismal ageing. 40,[63][64][65] Therefore, the molecular mechanism through which ΔNp63 exerts its antisenescence/antiageing functions may be mediated, at least in part, by the activation of antioxidant genes, including CYGB.…”