<i>DLX</i> Genes: Roles in Development and Cancer

• Main Authors: Yinfei Tan, Joseph R. Testa
• Format: Article
• Language: English
• Published: MDPI AG 2021-06-01
• Series: Cancers
• Subjects: homeobox genes; HOX; DLX; hematopoiesis; development; cancer
• Online Access: https://www.mdpi.com/2072-6694/13/12/3005

Homeobox genes control body patterning and cell-fate decisions during development. The homeobox genes consist of many families, only some of which have been investigated regarding a possible role in tumorigenesis. Dysregulation of <i>HOX</i> family genes have been widely implicated in cancer etiology. <i>DLX</i> homeobox genes, which belong to the NK-like family, exert dual roles in development and cancer. The <i>DLX</i> genes are the key transcription factors involved in regulating the development of craniofacial structures in vertebrates. The three <i>DLX</i> bigenes have overlapping expression in the branchial arches. Disruption of <i>DLX</i> function has destructive consequences in organogenesis and is associated with certain congenital disorders in humans. The role of <i>DLX</i> genes in oncogenesis is only beginning to emerge. DLX2 diminishes cellular senescence by regulating p53 function, whereas DLX4 has been associated with metastasis in breast cancer. In human ovarian cancer cells, DLX5 is essential for regulating AKT signaling, thereby promoting cell proliferation and survival. We previously implicated <i>Dlx5</i> as an oncogene in murine T-cell lymphoma driven by a constitutively active form of <i>Akt2</i>. In this mouse model, overexpression of <i>Dlx5</i> was caused by a chromosomal rearrangement that juxtaposed the Tcr-beta promoter region near the <i>Dlx5</i> locus. Moreover, transgenic mice overexpressing <i>Dlx5,</i> specifically in immature T-cells, develop spontaneous thymic lymphomas. Oncogenesis in this mouse model involves binding of Dlx5 to the <i>Notch1</i> and <i>Notch3</i> gene loci to activate their transcription. Dlx5 also cooperates with Akt signaling to accelerate lymphomagenesis by activating Wnt signaling. We also discuss the fact that human DLX5 is aberrantly expressed in several human malignancies.