Sine oculis homeobox 1 (SIX1), a key transcription factor for regulating aerobic glycolysis, participates in the occurrence of various cancer types. However, the role of SIX1 in melanoma and the upstream regulating mechanisms of SIX1 remain to be further investigated. MicroRNAs (miRNAs) have emerged as key regulators in tumorigenesis and progression. Here, we show that miR-489-3p suppresses SIX1 expression by directly targeting its 3′ untranslated region (3′ UTR) in melanoma cells. miR-489-3p suppressed melanoma cell proliferation, migration, and invasion through inhibition of SIX1. Mechanistically, by targeting SIX1, miR-489-3p dampens glycolysis, with decreased glucose uptake, lactate production, ATP generation, and extracellular acidification rate (ECAR), as well as an increased oxygen consumption rate (OCR). Importantly, glycolysis regulated by the miR-489-3p/SIX1 axis is critical for its regulation of melanoma growth and metastasis both in vitro and in vivo. In melanoma patients, miR-489-3p expression is negatively correlated with SIX1 expression. In addition, patients who had increased glucose uptake in tumors and with metastasis assessed by positron emission tomography (PET) scans showed decreased miR-489-3p expression and increased expression of SIX1. Collectively, our study demonstrates the importance of the miR-489-3p/SIX1 axis in melanoma, which can be a potential and a promising therapeutic target in melanoma.

正弦球同源盒1（SIX1），调节有氧糖酵解的关键转录因子，参与各种癌症类型的发生。然而，SIX1在黑色素瘤中的作用以及SIX1的上游调节机制仍有待进一步研究。微小RNA（miRNA）已成为肿瘤发生和发展中的关键调节因子。在这里，我们显示miR-489-3p通过直接靶向黑色素瘤细胞中的3'非翻译区（3'UTR）来抑制SIX1表达。miR-489-3p通过抑制SIX1抑制黑素瘤细胞的增殖，迁移和侵袭。从机械上讲，通过靶向SIX1，miR-489-3p可抑制糖酵解，减少葡萄糖摄取，乳酸生成，ATP生成和细胞外酸化率（ECAR），并增加耗氧率（OCR）。重要的，体外和体内。在黑色素瘤患者中，miR-489-3p表达与SIX1表达负相关。此外，在肿瘤中摄取葡萄糖增多并通过正电子发射断层扫描（PET）扫描评估有转移的患者显示，miR-489-3p表达降低，而SIX1表达升高。总的来说，我们的研究证明了miR-489-3p / SIX1轴在黑色素瘤中的重要性，它可能是黑色素瘤的潜在和有希望的治疗靶标。