Metabolic reprogramming promotes and sustains multiple steps of melanoma metastasis. Identification of key regulators of metabolic reprogramming could lead to the development of treatments for preventing and treating metastatic melanoma. Here, we identified that the tectonic family member TCTN1 promotes melanoma metastasis by increasing fatty acid oxidation (FAO). In clinical melanoma samples, high expression of TCTN1 correlated with increased metastasis and shorter patient survival. Functionally, TCTN1 promoted melanoma invasion and migration in vitro and distant metastasis in vivo, and TCTN1 induced a mesenchymal-like phenotype switch. Mechanistically, TCTN1 acted as a protein scaffold to promote the binding of HADHA and HADHB, subunits of the mitochondrial trifunctional protein complex, thus leading to FAO activation. TCTN1-mediated FAO activated the p38/MAPK signaling pathway in melanoma cells, promoting tumor EMT and stemness. Molecular docking indicated that the prostaglandin F receptor agonist fluprostenol can block HADHA/HADHB binding, which was confirmed experimentally. Treatment with fluprostenol was able to inhibit TCTN1-induced melanoma invasion and metastasis. Taken together, these findings elucidate the mechanism of TCTN1-mediated promotion of melanoma metastasis and support the potential application of fluprostenol for targeted therapy of metastatic melanoma.

中文翻译：

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TCTN1 诱导脂肪酸氧化促进黑色素瘤转移


代谢重编程促进并维持黑色素瘤转移的多个步骤。代谢重编程的关键调节因子的鉴定可能会导致预防和治疗转移性黑色素瘤的治疗方法的开发。在这里，我们发现构造家族成员 TCTN1 通过增加脂肪酸氧化 (FAO) 来促进黑色素瘤转移。在临床黑色素瘤样本中，TCTN1 的高表达与转移增加和患者生存期缩短相关。从功能上讲，TCTN1在体外促进黑色素瘤侵袭和迁移，在体内促进远处转移，并且TCTN1诱导间质样表型转换。从机制上讲，TCTN1 作为蛋白质支架促进线粒体三功能蛋白复合物亚基 HADHA 和 HADHB 的结合，从而导致FAO激活。 TCTN1介导的FAO激活黑色素瘤细胞中的p38/MAPK信号通路，促进肿瘤EMT和干性。分子对接表明前列腺素F受体激动剂氟前列醇可以阻断HADHA/HADHB结合，这一点已被实验证实。氟前列醇治疗能够抑制 TCTN1 诱导的黑色素瘤侵袭和转移。总而言之，这些发现阐明了 TCTN1 介导的促进黑色素瘤转移的机制，并支持氟前列醇用于转移性黑色素瘤靶向治疗的潜在应用。