The retinal determination gene network: from developmental regulator to cancer therapeutic target

Abstract

Although originally identified for its function in Drosophila melanogaster eye specification, the Retinal Determination Gene Network (RDGN) is essential for the development of multiple organs in mammals. The RDGN regulates proliferation, differentiation and autocrine signaling, and interacts with other key signaling pathways. Aberrant expression of RDGN members such as DACH, EYA and SIX contributes to tumor initiation and progression; indeed, the levels of RDGN members are clinically prognostic factors in various cancer types. Stimulation or suppression of the activities of these crucial components can block cancer cell proliferation, prevent cancer stem cell expansion and even reverse the EMT process, thereby attenuating malignant phenotypes. Thus, cancer therapeutic interventions targeting RDGN members should be pursued in future studies.

Keywords: DACH; EYA; SIX; prognosis; tumor growth.

Figure 1

A. RDGN members determine breast cancer initiation and progression. In normal breast epithelial cells, the functional balance of DACH and SIX/EYA maintains homeostasis in luminal cellular proliferation/apoptosis and thereby maintains the luminal structure. Functional loss of DACH or hyperactivity of SIX/EYA drives hyper-proliferation, transformation, and progression to ductal carcinoma in situ. Some malignant cells undergo EMT, acquire cancer stem cell properties, invade through the basal membrane and enter blood vessels, leading to distant metastases. “↑” represents an upregulated function and “↓” represents a downregulated function.

Figure 2. Targeting the DACH/SIX/EYA pathway in cancer treatment

TGFβ and Wnt signaling are both critical for tumor initiation and progression. Generally, SIX/EYA activates these two signaling pathways, whereas DACH1 negatively regulates them. The function of SIX could be blocked by the silencing of SIX expression with shRNA, or by the disruption of the SIX/EYA complex with small molecules. EYA phosphatase activity could be blocked by biochemical inhibitors. On the other hand, DACH1 expression could be reactivated with demethylating agents or miRNA. Thus, targeting RDGN members is a promising therapeutic strategy that could restrain malignant behavior in tumors.