Lau Eric, Feng Yongmei, Claps Giuseppina, Fukuda Michiko N, Perlina Ally, Donn Dylan, Jilaveanu Lucia, Kluger Harriet, Freeze Hudson H, Ronai Ze'ev A
Tumor Initiation and Maintenance Program, Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
Department of Internal Medicine, Section of Medical Oncology, Yale University, New Haven, CT 06520, USA.
Sci Signal. 2015 Dec 8;8(406):ra124. doi: 10.1126/scisignal.aac6479.
Melanoma is one of the most lethal skin cancers worldwide, primarily because of its propensity to metastasize. Thus, the elucidation of mechanisms that govern metastatic propensity is urgently needed. We found that protein kinase Cε (PKCε)-mediated activation of activating transcription factor 2 (ATF2) controls the migratory and invasive behaviors of melanoma cells. PKCε-dependent phosphorylation of ATF2 promoted its transcriptional repression of the gene encoding fucokinase (FUK), which mediates the fucose salvage pathway and thus global cellular protein fucosylation. In primary melanocytes and cell lines representing early-stage melanoma, the abundance of PKCε-phosphorylated ATF2 was low, thereby enabling the expression of FUK and cellular protein fucosylation, which promoted cellular adhesion and reduced motility. In contrast, increased expression of the gene encoding PKCε and abundance of phosphorylated, transcriptionally active ATF2 were observed in advanced-stage melanomas and correlated with decreased FUK expression, decreased cellular protein fucosylation, attenuated cell adhesion, and increased cell motility. Restoring fucosylation in mice either by dietary fucose supplementation or by genetic manipulation of murine Fuk expression attenuated primary melanoma growth, increased the number of intratumoral natural killer cells, and decreased distal metastasis in murine isograft models. Tumor microarray analysis of human melanoma specimens confirmed reduced fucosylation in metastatic tumors and a better prognosis for primary melanomas that had high abundance of fucosylation. Thus, inhibiting PKCε or ATF2 or increasing protein fucosylation in tumor cells may improve clinical outcome in melanoma patients.
黑色素瘤是全球最致命的皮肤癌之一，主要原因是其易于转移。因此，迫切需要阐明控制转移倾向的机制。我们发现蛋白激酶Cε（PKCε）介导的激活转录因子2（ATF2）的激活控制着黑色素瘤细胞的迁移和侵袭行为。PKCε依赖的ATF2磷酸化促进了其对编码岩藻糖激酶（FUK）基因的转录抑制，FUK介导岩藻糖挽救途径，从而介导整体细胞蛋白岩藻糖基化。在原代黑素细胞和代表早期黑色素瘤的细胞系中，PKCε磷酸化的ATF2丰度较低，从而使FUK得以表达和细胞蛋白岩藻糖基化，促进细胞黏附并降低运动性。相反，在晚期黑色素瘤中观察到编码PKCε的基因表达增加以及磷酸化的、具有转录活性的ATF2丰度增加，这与FUK表达降低、细胞蛋白岩藻糖基化减少、细胞黏附减弱和细胞运动性增加相关。通过饮食补充岩藻糖或对小鼠Fuk表达进行基因操作来恢复小鼠的岩藻糖基化，可减弱原发性黑色素瘤的生长，增加肿瘤内自然杀伤细胞的数量，并减少小鼠异种移植模型中的远处转移。对人类黑色素瘤标本的肿瘤微阵列分析证实，转移性肿瘤中的岩藻糖基化减少，而岩藻糖基化丰度高的原发性黑色素瘤预后较好。因此，抑制肿瘤细胞中的PKCε或ATF2或增加蛋白岩藻糖基化可能会改善黑色素瘤患者的临床结局。
