Role of MTA2 in human cancer

Abstract

Metastasis is the ultimate cause of death for most cancer patients. While many mechanisms have been delineated for regulation of growth and tumor initiation of the primary tumor, very little is known about the process of metastasis. Metastasis requires dynamic alteration of cellular processes in order for cells to disseminate from the primary tumor to distant sites. These alterations often involve dramatic changes in the regulation of cytoskeletal and cell-environment interactions. Furthermore, controlled refinement of these interactions requires feedback to regulatory networks in the nucleus. MTA2 is a member of the metastasis tumor-associated family of transcriptional regulators and is a central component of the nucleosome remodeling and histone deacetylation complex. MTA2 acts as a central hub for cytoskeletal organization and transcription and provides a link between nuclear and cytoskeletal organization. We will focus on MTA2 in this chapter, especially its role in breast cancer metastasis.

Figure 1. Gene organization and mutational landscape of MTAs

Each MTA family member is shown along the x axis, amino acid coordinates are indicated. BAH, ELM2, and GATA domains are indicated on each gene. Point mutations reported in cBioProtal are indicated and the frequency of mutations at those sites is shown on the y axis. Missense mutations are indicated in green and inactivating mutations (frame-shift and nonsense) are shown in red (purple is the combination of green and red).

Figure 2. MTA2 in the NuRD complex

NuRD complex components are shown with key MTA2 targets indicated, ER-alpha, p53, and transcriptional regulation.

Figure 3. MTA2 variation in cancer

Mutations and CNV alterations are shown as reported from cBioPortal. Bar colors are indicated in the key.

Figure 4. Cytoskeletal changes associated with MTA2 overexpression and ROCK inhibition

MTA2-overexpressing or vector control cells are shown treated with either vehicle or H-1152, a potent ROCK inhibitor. Cells were stained for p-LIMK1/2 (green), phaloidin (red), and DAPI (blue). Pseudopodia are indicated with white arrows, lamelopodia are indicated with red arrows.