DLX5 (Distal-less Homeobox 5) Promotes Tumor Cell Proliferation by Transcriptionally Regulating MYC

Cancer Signaling and Genetics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 07/2009; 284(31):20593-601. DOI: 10.1074/jbc.M109.021477
Source: PubMed


The human DLX homeobox genes, which are related to Dll (Drosophila distal-less gene), encode transcription factors that are expressed primarily in embryonic development. Recently, DLX5 was reported to act as an oncogene in lymphomas and lung cancers, although the mechanism is not known. The identification
of target genes of DLX5 can facilitate our understanding of oncogenic mechanisms driven by overexpression of DLX5. The MYC oncogene is aberrantly expressed in many human cancers and regulates transcription of numerous target genes involved in tumorigenesis.
Here we demonstrate by luciferase assay that the MYC promoter is specifically activated by overexpression of DLX5 and that two DLX5 binding sites in the MYC promoter are important for transcriptional activation of MYC. We also show that DLX5 binds to the MYC promoter both in vitro and in vivo and that transfection of a DLX5 expression plasmid promotes the expression of MYC in a dose-dependent manner in mammalian
cells. Furthermore, overexpression of DLX5 results in increased cell proliferation by up-regulating MYC. Knockdown of DLX5
in lung cancer cells overexpressing DLX5 resulted in decreased expression of MYC and reduced cell proliferation, which was
rescued by overexpression of MYC. Because DLX5 has a restricted pattern of expression in adult tissues, it may serve as a
potential therapeutic target for the treatment of cancers that overexpress DLX5.

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    • "Already before gastrulation, the non-neural ectoderm expresses transcription factors of the Ap2 (Hoffman et al., 2007; Knight et al., 2003, 2005; Li and Cornell, 2007; Luo et al., 2003; Werling and Schorle, 2002; see review: Eckert et al., 2005), Foxi (Foxi1 in fish (Solomon et al., 2003a) and Xenopus (Matsuo-Takasaki et al., 2005; see review: Pohl and Knochel, 2005; Pohl et al., 2002; Suri et al., 2005); Foxi3 in mouse (Ohyama and Groves, 2004), Gata2 and -3 (Dirksen et al., 1994; Neave et al., 1995; Sheng and Stern, 1999) and Dlx families (Dlx3/4 in teleost (Solomon and Fritz, 2002), Dlx5/6 in amniotes (Brown et al., 2005; Davideau et al., 1999; McLarren et al., 2003; Quint et al., 2000; Simeone et al., 1994; Stock et al., 1996; Zhang et al., 1997; see review: Kraus and Lufkin, 1999; Merlo et al., 2000) or Dlx3/5 in Xenopus (Akimenko et al., 1994; Dirksen et al., 1993; Luo et al., 2001a,b; Woda et al., 2003). These are activated downstream of BMP signalling (Beanan and Sargent, 2000; Luo et al., 2001b; Mir et al., 2007; Pohl and Knochel, 2005; Suri et al., 2005; see review: Xu and Testa, 2009) prior to the onset of Six1/4 and Eya1/2 and are cell autonomously required for the activation of their expression (Kwon et al., 2010; Pieper et al., 2012). In Xenopus, ectopic Dlx3 or Gata2 expression broadens Six1 and Eya2, while repressing the neural marker Sox3 and the neural crest markers Msx1, Pax3 and Zic1. "
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    • "In addition, Dlx-5 is also unregulated in several human solid tumors, including lung, breast, and ovarian cancers, and T-cell lymphomas, and contributes to tumor progression [26-29]. Dlx-5 has been shown to promote tumor cell proliferation by directly binding the MYC promoter and upregulating MYC [30]. Dlx-7 is also known to regulate MYC expression in erythroleukemia cells [31]. "
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