Epigenetic, Genetic, and Acquired Regulation of Cav3 T-Type Calcium Channel Expression and Function in Tumor Growth and Progression

T-type Ca2+ channels are a specific channel family controlling proliferation, differentiation, angiogenesis, and invasion of tumor cells. Molecular biology has identified three main subfamilies of α1 subunits, called Cav1, Cav2, and Cav3. The third subfamily contains three members, called T-types: Cav3.1 (α1G), Cav3.2 (α1H), and Cav3.3 (α1I). The Cav3 channels are expressed in normal tissues throughout the body as well as in different types of tumors such as breast, glioma/neuroblastomas, colorectal, gastric, hepatic and prostate tumors, T cell leukemia, retinoblastoma (RB), and phaeochromocytoma. It has been shown that increased functional expression of Cav3 channels plays a role in abnormal proliferation of tumor cells. In addition, a crosstalk between the Rho-ROCK pathway and Cav3 channels in tumor cell migration and invasion has been demonstrated. Cav3 expression is strictly regulated during cell differentiation and tumor formation. Inactivation of Cav3 genes by aberrant methylation plays a major role in tumor development and progression. In this regard, since hypermethylation of CpG islands is thought to be the major epigenetic modification repressing gene transcription, Cav3.1 has been regarded as a candidate tumor suppressor gene. In contrast, CpG sites in the Cav3.2 gene were hypomethylated, and thus this gene is considered to be a candidate oncogene, regulated by methylation. Finally, Cav3 functional diversity may also result from the generation of splice variants. Alterations in the expression of different splice variants, and their expression during tumor development and progression, may trigger variety in Ca2+ signaling, which may contribute to the generation of more aggressive tumor clones.