Antagonism of HOX/PBX Dimer Formation Blocks the In vivo Proliferation of Melanoma

Abstract

Malignant melanoma is a cancer that arises from melanocyte cells in a complex but well-studied process, and which can only be successfully treated prior to metastasis as it is highly resistant to conventional therapies. A number of recent reports have indicated that members of the HOX family of homeodomain-containing transcription factors are deregulated in melanoma, and may actually be required to maintain proliferation. In this report, we describe the use of a novel, cell-permeable antagonist of the interaction between HOX proteins and PBX, a second homeodomain-containing transcription factor that modifies HOX activity. This antagonist can block the growth of murine B16 cells and trigger apoptosis both in vitro and in vivo when administered to mice with flank tumors. [Cancer Res 2007;67(12):5806-13]

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

“…Given the high level of HOX expression in primary tumours and A549 and H23 cells, we investigated whether HXR9 could trigger cell death in a similar manner to that observed for melanoma cells (Morgan et al, 2007). Treatment of cultures with HXR9 (60 mM) for 3 h resulted in a high degree of cell death whereas CXR9 had no discernable effects.…”

“…HXR9 is an 18-amino-acid peptide consisting of the previously identified hexapeptide sequence that can bind to PBX and nine C-terminal arginine residues (R9) that facilitate cell entry (Morgan et al, 2007). The N-terminal and C-terminal amino bonds are in the D-isomer conformation, which has earlier been shown to extend the half-life of the peptide to 12 h in human serum (Morgan et al, 2007).…”

“…The N-terminal and C-terminal amino bonds are in the D-isomer conformation, which has earlier been shown to extend the half-life of the peptide to 12 h in human serum (Morgan et al, 2007). CXR9 is a control peptide that lacks a functional hexapeptide sequence and that includes the R9 sequence.…”

“…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.…”

“…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.…”