Mitf regulation of Dia1 controls melanoma proliferation and invasiveness

Abstract

It is widely held that cells with metastatic properties such as invasiveness and expression of matrix metalloproteinases arise through the stepwise accumulation of genetic lesions arising from genetic instability and "clonal evolution." By contrast, we show here that in melanomas invasiveness can be regulated epigenetically by the microphthalmia-associated transcription factor, Mitf, via regulation of the DIAPH1 gene encoding the diaphanous-related formin Dia1 that promotes actin polymerization and coordinates the actin cytoskeleton and microtubule networks at the cell periphery. Low Mitf levels lead to down-regulation of Dia1, reorganization of the actin cytoskeleton, and increased ROCK-dependent invasiveness, whereas increased Mitf expression leads to decreased invasiveness. Significantly the regulation of Dia1 by Mitf also controls p27 The ability of cancer cells to acquire properties of invasiveness and the potential to metastasize is not entirely understood. In the traditional model, genetic instability within a tumor would lead within some cells to the accumulation of genetic and stable epigenetic lesions that are compatible with increased invasiveness and metastatic potential. These genetic lesions and stable epigenetic modifications, such as histone and DNA methylation, would be inherited by the metastatic progeny and dictate alterations in gene expression compatible with metastatic potential (for a review, see Baylin and Ohm 2006). Alternatively, invasive potential could represent a specific epigenetic state that is inherently unstable and nonheritable, being imposed by the microenvironment of the cell; in this model, properties associated with metastasis may be lost once the invasive cell has taken up residence in another location. While considerable resources have been expended on trying to pinpoint genetic mutations that correlate with metastatic potential and, more recently, the resulting stable epigenetic changes, the molecular mechanisms that would underpin a dynamic epigenetic model for cancer metastasis have been relatively little explored.Some cancer types, such as melanoma, are intrinsically more metastatic than others, and it has been postulated that the ability of melanomas to invade and proliferate may be related to the inherent ability of melanoblasts to migrate from the neural crest and proliferate to populate the epidermis and hair follicles Gupta et al. 2005). Some genes have been identified whose expression appears to correlate with the ability of melanomas to metastasize. The expression of SLUG, for example, can promote metastasis and facilitates the loss of E-cadherin (Gupta et al. 2005), a key molecule that mediates melanocyte adhesion to keratinocytes that is lost when melanomas acquire invasive potential (Haass et al. 2005), while NEDD9, an adaptor protein that interacts with focal adhesion kinase, is frequently overexpressed in metastatic melanoma and promotes invasiveness (Kim et al. 2006). However, despite these advances, and some preliminary investigations into the concept tha...

Aberrant miR-182 expression promotes melanoma metastasis by repressing FOXO3 and microphthalmia-associated transcription factor

“…In addition to its role in differentiation, MITF represses cell proliferation by activating the expression of cell-cycle inhibitors, such as p16 INK4a (26) and p21 Cip1 (27). Furthermore, MITF has been directly linked to the control of cell migration by regulating DIA1, which coordinates the actin cytoskeleton and microtubule networks at the cell periphery (28). Accordingly, MITF down-regulation by shRNA enhanced the in vivo metastatic behavior of B16 cells (Fig.…”

High-throughput physical phenotyping of cell differentiation

“…There have been studies demonstrating changes in expression of several genes and transcription factors (e.g., cathepsin D, Pax 6, calbindin, PKC-a, and Mitf) during pluripotent stem cell differentiation 34,35 ; many of these contribute to the organization of the cytoskeleton through microfilaments, intermediate filaments, and/or microtubules [36][37][38][39][40][41][42][43] . For example, upregulation of Pax6 or PKC-a during differentiation may stabilize the cytoskeleton 44,45 .…”

β-Catenin induces immortalization of melanocytes by suppressing p16INK4a expression and cooperates with N-Ras in melanoma development

“…Recent evidence has revealed that low levels of Mitf activity can promote proliferation (Carreira et al 2006) while high levels inhibit cell division (Carreira et al 2005;Loercher et al 2005;Wellbrock and Marais 2005). Since ␤-catenin can directly activate the Mitf-M promoter via a LEF/Tcf-binding site (Takeda et al 2000), any activation of ␤-catenin would either promote or inhibit proliferation depending on the basal level of Mitf activity in the cell.…”