Abstract
Microphthalmia-associated transcription factor (MITF) is the principal transcription factor regulating pivotal processes in melanoma cell development, growth, survival, proliferation, differentiation and invasion. In recent years, convincing evidence has been provided attesting key roles of endolysosomal cation channels, specifically TPCs and TRPMLs, in cancer, including breast cancer, glioblastoma, bladder cancer, hepatocellular carcinoma and melanoma. In this review, we provide a gene expression profile of these channels in different types of cancers and decipher their roles, in particular the roles of two-pore channel 2 (TPC2) and TRPML1 in melanocytes and melanoma. We specifically discuss the signaling cascades regulating MITF and the relationship between endolysosomal cation channels, MAPK, canonical Wnt/GSK3 pathways and MITF.
Highlights
Endolysosomal Cation Channels and Melanocytes are neural-crest derived cells that produce melanin, the primary determinant of skin color
Microphthalmia-associated transcription factor (MITF) is a central player of melanocyte survival, function and development [27,28,29]. It belongs to the MiT/TFE family of transcription factors in vertebrates, consisting of four distinct but closely related and evolutionary conserved members, including MITF, transcription factor EB (TFEB), TFE3 and TFEC
MITF encodes a basic–helix–loop–helix leucine zipper transcription factor, thereby exerting its function by regulating genes involved in cell cycle progression and differentiation, a role sustained throughout the process of melanogenesis and in melanoma [30,31,32]
Summary
Endolysosomal Cation Channels and Melanocytes are neural-crest derived cells that produce melanin, the primary determinant of skin color. Two human TPC2 gain-of-function (GOF) variations were identified as associated with blond hair color: rs35264875 (encoding M484L), which results in an increased sensitivity to the endogenous TPC2 ligand PI(3,5)P2 , while rs3829241 (encoding G734E) results in reduced channel inhibition by ATP [8,10,13]. Knockout of TPC2 results in a strong increase in melanin production in both primary human melanocytes and in pigmented melanoma cells (i.e., MNT-1) [7]. It is well-established that melanin is one of the major protective factors against UV radiation mediated DNA damage that results in melanoma development [15]. While common consensus suggests that knockout, knockdown, or pharmacological inhibition of TPCs, and in particular TPC2, reduces cancer cell migration, invasion and proliferation, including melanoma cells, some report otherwise
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