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

Abstract

Oxidative stress contributes to both aging and tumorigenesis. The transcription factor Bach1, a regulator of oxidative stress response, augments oxidative stress by repressing the expression of heme oxygenase-1 (HO-1) gene (Hmox1) and suppresses oxidative stress-induced cellular senescence by restricting the p53 transcriptional activity. Here we investigated the lifelong effects of Bach1 deficiency on mice. Bach1-deficient mice showed longevity similar to wild-type mice. Although HO-1 was upregulated in the cells of Bach1-deficient animals, the levels of ROS in Bach1-deficient HSCs were comparable to those in wild-type cells. Bach1 −/−; p53 −/− mice succumbed to spontaneous cancers as frequently as p53-deficient mice. Bach1 deficiency significantly altered transcriptome in the liver of the young mice, which surprisingly became similar to that of wild-type mice during the course of aging. The transcriptome adaptation to Bach1 deficiency may reflect how oxidative stress response is tuned upon genetic and environmental perturbations. We concluded that Bach1 deficiency and accompanying overexpression of HO-1 did not influence aging or p53 deficiency-driven tumorigenesis. Our results suggest that it is useful to target Bach1 for acute injury responses without inducing any apparent deteriorative effect.

The BACH1–HMOX1 Regulatory Axis Is Indispensable for Proper Macrophage Subtype Specification and Skeletal Muscle Regeneration

“…BACH1 is ubiquitously expressed in most MFs and has been predicted to be among the core regulators of MF identity along with TCEF3, C/ EBPa, and CREG-1 (60,61,63). However, contrary to expectations based on its importance and ubiquitous presence, the existing mouse model has minimal MF developmental defects and no overall physiological defects in mouse development and lifespan (64,65). In addition, in experimental injury and inflammatory models, these animals show protective phenotypes and dampened overall inflammatory responses (64,66,67).…”

Bach1 deficiency reduces severity of osteoarthritis through upregulation of heme oxygenase-1

“…In the present study, Bach1 -/- mice exhibited highly increased HO-1 expression even in articular cartilage of aged mice and reduced severity of age-related OA-like changes. However, Bach1 deficiency and accompanying overexpression of HO-1 did not influence aging and life span [ 27 ]. Inflammation and obesity generally increase with aging.…”

Bach1: Function, Regulation, and Involvement in Disease

“…Bach1 also suppresses the expression of transketolase (TKT), an enzyme that is required for the growth of hepatic cancer cells because it participates in the pentose phosphate pathway and in the production of the antioxidant molecule NADPH [ 58 ]. Furthermore, although oxidative stress is known to contribute to both aging and tumorigenesis and Bach1 deficiencies increase HO-1 expression, Bach1 does not appear to influence aging in mice and the rate of spontaneous tumorigenesis in p53-deficient mice and in Bach1-p53 double-deficient mice was similar [ 59 ]. Thus, Bach1 function differs between different cancer cell types, even within the same cell type (e.g., breast cancer cells), and Bach1 may have a different effect on cancer cell growth and cancer metastasis [ 53 , 57 ].…”