Necdin: A multi functional protein with potential tumor suppressor role?

Abstract

Necdin (NDN), a member of the melanoma-associated antigen (MAGE) family of proteins was first identified in mouse stem cells of embryonal carcinoma origin induced to differentiate by treatment with retinoic acid. The human gene maps to chromosome 15q11. This imprinted region is implicated in the pathogenesis of Prader-Willi syndrome (PWS), a neurodevelopmental disorder, where NDN is one of multiple genes silenced by deletion, maternal uniparental disomy or translocation. Due to this association, much interest has focused on the role of NDN in neuronal development and differentiation. However, a considerable number of studies have identified additional functions of NDN. Taken together these studies suggest a pleiotropic protein with diverse functions some of which may be relevant to tumorigenesis. Downregulation of NDN occurs in carcinoma cell lines and primary tumors, suggesting a tumor suppressor role. Our working hypothesis is that NDN is a worthy candidate for further studies with regard to a potential tumor suppressor role. In this article we outline the considerable evidence supporting the hypothesis that NDN has multiple functions, some of which indicate that it could be a tumor suppressor. The roles of NDN in key processes such as interaction with p53 and E2F-1, hematopoietic stem cell quiescence, transcriptional repression, angiogenesis, differentiation and interaction with the polycomb group gene BMI1 are discussed. Confirmation of NDN as a tumor suppressor may have implications for monitoring of PWS patients and could present a novel cancer therapeutic target.

Necdin enhances muscle reconstitution of dystrophic muscle by vessel-associated progenitors, by promoting cell survival and myogenic differentiation

“…Necdin has been also suggested having a role as a tumor suppressor gene. 32 Long-term studies on mice overexpressing necdin or on immunodeficient mice injected with cells overexpressing necdin will be certainly required to address this issue.…”

Cross-Analysis of Gene and miRNA Genome-Wide Expression Profiles in Human Fibroblasts at Different Stages of Transformation

“…Necdin (NDN) was highly downregulated from PD 97 (logFC < -4.7); this gene has tumor suppressive functions and was found to be downregulated also in telomerase immortalized urothelial cells (Chapman and Knowles, 2009). …”

“…NDN is a potential tumor suppressor gene, being downregulated in several types of tumors, and can modulate gene expression interacting with the transcription factor E2F1 (Chapman and Knowles, 2009). In our cellular system, a decrease in the expression of the cyclin-dependent kinase inhibitors CDKN2A and CDKN1C was an early event during transformation, followed by the accumulation of additional changes in the expression of cell cycle and cell proliferation genes, together with changes in genes involved in chromosome maintenance and segregation.…”

Specific changes in the expression of imprinted genes in prostate cancer—implications for cancer progression and epigenetic regulation

“…206 In summary, necdin, on the one hand, has a potential to function as a tumour suppressor by inhibiting the cell cycle, but on the other hand, it might promote cell survival during stress by its attenuating effect on p53. 207 The function of necdin in the prostate and in human cancers is poorly studied.…”