Melanoma arising from pigment-producing melanocytes is the deadliest form of skin cancer. Extensive ultraviolet light exposure is a major cause of melanoma and individuals with low levels of melanin are at particular risk. Humans carrying gain-of-function polymorphisms in the melanosomal/endolysosomal two-pore cation channel TPC2 present with hypopigmentation, blond hair, and albinism. Loss of TPC2 is associated with decreased cancer/melanoma proliferation, migration, invasion, tumor growth and metastasis formation, and TPC2 depleted melanoma cells show increased levels of melanin. How TPC2 activity is controlled in melanoma and the downstream molecular effects of TPC2 activation on melanoma development remain largely elusive. Here we show that the small GTPase Rab7a strongly enhances the activity of TPC2 and that effects of TPC2 on melanoma hallmarks, in vitro and in vivo strongly depend on the presence of Rab7a, which controls TPC2 activity to modulate GSK3β, β-Catenin, and MITF, a major regulator of melanoma development and progression.

由产生色素的黑色素细胞引起的黑色素瘤是最致命的皮肤癌形式。广泛的紫外线照射是黑色素瘤的主要原因，黑色素水平低的个体尤其危险。在黑色素体/内溶酶体双孔阳离子通道 TPC2 中携带功能获得性多态性的人类表现为色素减退、金发和白化病。TPC2 的缺失与癌症/黑色素瘤增殖、迁移、侵袭、肿瘤生长和转移形成减少有关，TPC2 耗尽的黑色素瘤细胞显示黑色素水平升高。黑色素瘤如何控制 TPC2 活性以及 TPC2 激活对黑色素瘤发展的下游分子效应在很大程度上仍然难以捉摸。在这里，我们表明小 GTP 酶 Rab7a 强烈增强 TPC2 的活性，并且 TPC2 在体外和体内对黑色素瘤标志物的影响在很大程度上取决于 Rab7a 的存在，Rab7a 控制 TPC2 活性以调节 GSK3β、β-连环蛋白和 MITF，这是黑色素瘤发展和进展的主要调节因子。