HOX transcription factors are potential therapeutic targets in non-small-cell lung cancer (targeting HOX genes in lung cancer)

Abstract

The HOX genes are a family of homeodomain-containing transcription factors that determine the identity of cells and tissues during embryonic development. They are also known to behave as oncogenes in some haematological malignancies. In this study, we show that the expression of many of the HOX genes is highly elevated in primary non-small-cell lung cancers (NSCLCs) and in the derived cell lines A549 and H23. Furthermore, blocking the activity of HOX proteins by interfering with their binding to the PBX co-factor causes these cells to undergo apoptosis in vitro and reduces the growth of A549 tumours in vivo. These findings suggest that the interaction between HOX and PBX proteins is a potential therapeutic target in NSCLC. The HOX genes are a family of homeodomain-containing transcription factors that determine the identity of cells and tissues in early development (Iimura and Pourquié, 2007), and also have key regulatory roles in adult haematopoietic stem cells and their descendants (Abramovich and Humphries, 2005). In addition, HOX genes are often overexpressed in malignant cells and are known to act as oncogenes in some haematopoietic malignancies (Eklund, 2007).Repeated duplication events have given rise to 39 HOX genes in mammals, divided into four groups (A -D) in tightly linked clusters on different chromosomes (Hoegg and Meyer, 2005). The HOX genes are also divided into paralogue groups -genes that have the equivalent position in each cluster (1 -13) -thus HOXA1, for example, is the 3 0 most gene in cluster A (Scott, 1993). Whereas some HOX genes have distinct functions in specific contexts, many others have overlapping or redundant functions, both during early development (McIntyre et al, 2007) and in malignant cells (Eklund, 2007). This redundancy in HOX function is based in part upon the binding of similar DNA sequences and also on the interaction of HOX proteins with a common set of co-factors including PBX and MEIS. PBX and MEIS modify the DNA-binding specificity of HOX proteins, influence the regulation of transcription and are required for many aspects of HOX function (Moens and Selleri, 2006).In addition to haematological malignancies, the HOX genes are also expressed at high levels in many other solid malignancies, although with the exception of melanoma (Morgan et al, 2007), they are not known to have an oncogenic function. A number of studies, focusing on small groups of HOX genes, have shown that some are upregulated in lung cancer (Abe et al, 2006), but the functional significance of this is unknown. Here we present a comprehensive analysis of HOX expression in non-small-cell lung cancer (NSCLC) that reveals that many of the HOX genes have strongly elevated expression in malignant cells. Further, we show that antagonising HOX/PBX binding in the NSCLC cell lines A549 (Lieber et al, 1976) and H23 (Little et al, 1983) induces apoptosis in vitro and causes significant tumour shrinkage in A549 nude mouse models.

Long noncoding RNA-HOTAIR affects chemoresistance by regulating HOXA1 methylation in small cell lung cancer cells

“…13 Our previous study showed that HOXA1, targeted by miR-100, played a role in SCLC cell survival and chemoresistance. 14 HOXA1 was found to stimulate STAT3 and STAT5B in oncogenic transformation of the immortalized mammary epithelial cells, 15 and regulated the p44/42 MAP kinase pathway in mammary cancer cells. 16 The overexpression of HOXA1 was associated with poor outcome in patients with HCC, whereas the downregulation of HOXA1 can inhibit cell growth, anchorage-independent growth, migration, and invasion of HepG2 cells.…”

Expression level of pre-B-cell leukemia transcription factor 2 (PBX2) as a prognostic marker for gingival squamous cell carcinoma

“…VCP is involved in the regulation of activation of nuclear factor kappa B (NFκB) (Naora et al, 2001;Takahashi et al, 2007), which is a transcription factor correlated with various cellular activities such as anti-apoptosis, and cell proliferation and invasion (Plowright et al, 2009). Univariate analysis revealed that expressions of VCP and PBX2 were significant factors for both DFS and OS.…”

Expression level of Pre B cell leukemia homeobox 2 correlates with poor prognosis of gastric adenocarcinoma and esophageal squamous cell carcinoma

“…Potts et al reported that HOX protein ensures cell survival by inhibition of apoptosis, thus promotes leukemia development (39). Decreased activity of HOX proteins by interfering their binding to the PBX co-factor causes apoptosis of cancer cell lines in vitro and reduces the growth in vivo (15,40).…”

“…In contrast to other HOX proteins, PBX family proteins have not been studied in detail. The interference of PBX binding to HOX proteins yielded apoptosis and reduced growth activity of tumors in vivo, indicating that the interaction of PBX to HOX appears to be crucial in tumor behavior (15)(16)(17).…”