A Role for the HOXB7 Homeodomain Protein in DNA Repair

Abstract

Homeobox genes encode transcription factors which function in body axis patterning in the developing embryo. Recent evidence suggests that the maintenance of specific HOX expression patterns is necessary for regulating the homeostasis of adult tissues as well. In this study, HOXB7 transformed human mammary epithelial cells, MCF10A, to grow in minimally supplemented medium, to form colonies in Matrigel, and display resistance to ionizing radiation. Searching for protein partners of HOXB7 that might contribute to resistance to ionizing radiation, we identified four HOXB7-binding proteins by GST pull-down/affinity chromatography and confirmed their interactions by coimmunoprecipitation in vivo. Interestingly, all four HOXB7-binding proteins shared functions as genomic caretakers and included members of the DNA-dependent protein kinase holoenzyme (Ku70, Ku80, DNA-PK cs ) responsible for DNA double-strand break repair by nonhomologous end joining pathway and poly(ADP) ribose polymerase. Exogenous and endogenous expression of HOXB7 enhanced nonhomologous end joining and DNA repair functions in vitro and in vivo, which were reversed by silencing HOXB7. This is the first mechanistic study providing definitive evidence for the involvement of any HOX protein in DNA double-strand break repair. [Cancer Res 2007;67(4):1527-35]

HOXB7 Predicts Poor Clinical Outcome in Patients with Advanced Esophageal Squamous Cell Cancer

“…Though we failed to investigate the potential molecular mechanism for the limited experimental conditions, the prognostic role of HOXB7 could be supported by several previous molecular studies suggesting its role in esophageal cancer proliferation (Xie et al, 2013), DNA repairing (Rubin et al, 2007), cell motility (Srebrow et al, 1998).…”

“…The expression of HOX genes keeps to temporal and spatial colinearity in embryonic development (Shah and Sukumar, 2010). Aberrant expression of HOX genes was found in various types of cancer, such as ovarian cancer (Yamashita et al, 2006), leukemia (Chang et al, 1997), breast cancer (Jin et al, 2012), cervical cancer (How et al, 2013), prostate cancer (Rubin et al, 2007), melanoma (Care et al, 1996), oral squamous cell cancer (De Souza Setubal Destro et al, 2010) and esophageal squamous cell cancer (Gu et al, 2009). However, the detailed relationship between HOX genes and tumorigenesis remains unclear (Shah and Sukumar, 2010).…”

“…Moreover, overexpression of HOXB7 was associated with poor prognosis of breast cancer (Srebrow et al, 1998), colorectal cancer (Liao et al, 2011) and oral squamous cell cancer (Xie et al, 2013). Molecular and biochemical studies indicated that HOXB7 could promote proliferation of esophageal cancer cells (Xie et al, 2013), interact with proteins about DNA repair (Rubin et al, 2007), promote transforming ability in human breast epithelial cells (Srebrow et al, 1998).…”

Influence of Hoxa5 on p53 Tumorigenic Outcome in Mice

“…Consequently, changes in Hox gene expression in various cancers have been associated to altered proliferation, angiogenesis, apoptosis, DNA repair, and metastatic behavior. [15][16][17][18][19] Increased incidence of malignancies correlates also with ectopic cervical ribs in humans, a skeletal transformation associated with several loss-of-Hox gene function mutations, suggesting that Hox genes might be a molecular link between congenital anomalies and cancer. 20 p53 gene expression has been shown to be under the control of HOX proteins.…”

HOX transcription factors and the prostate tumor microenvironment

“…DUSP1 is a tumour suppressor gene [30] , and whilst cFos is generally considered to be a protoncogene, cFos protein can also induce apoptosis through the activation of the cell death ligand, FAS1 [31][32][33][34][35] . Additional cellular functions of individual HOX proteins include DNA repair [36] and the regulation of the cell cycle [37] . It has also become apparent that the HOX genes function to modify the tumour microenvironment, and it is this aspect of their biology that we focus on here.…”