含有 88C (CCDC88C) 的卷曲螺旋结构域是非经典 Wnt 信号传导的一个组成部分，其失调会导致结直肠癌转移。在乳腺癌淋巴结转移肿瘤组织中观察到CCDC88C表达失调。然而，CCDC88C 在乳腺癌转移中的作用仍不清楚。为了解决这个问题，开发了具有 CCDC88C 过表达或敲低的稳定 BT549 和 SKBR3 细胞系。功能丧失/获得实验表明，CCDC88C 在体外驱动乳腺癌细胞运动，在体内驱动肺和肝转移。我们发现 CCDC88C 导致 c-JUN 诱导的转录激活。从 CCDC88C 和 c-JUN 调节的基因中鉴定出重叠基因。 CEMIP 是这些重叠基因之一，已被证实会导致乳腺癌转移。我们发现CCDC88C通过c-JUN调节CEMIP mRNA水平，并且它以CEMIP依赖性方式发挥促转移能力。此外，我们还鉴定出 CCDC88C 是多肽 N-乙酰半乳糖氨基转移酶 6 (GALNT6) 的底物。 GALNT6与正常乳腺癌和乳腺癌组织中CCDC88C蛋白丰度呈正相关，表明GALNT6可能与乳腺癌中CCDC88C的表达模式相关。我们的数据表明，GALNT6 通过促进其 O-连接糖基化来维持 CCDC88C 的稳定性，并且该修饰对于 CCDC88C 的促转移潜力至关重要。 CCDC88C 还可以介导 GALNT6 在乳腺癌中的促转移潜力。总的来说，我们的研究结果表明 CCDC88C 可能会增加乳腺癌转移的风险，并阐明了潜在的分子机制。© 2024。作者。

Coiled-coil domain containing 88C (CCDC88C) is a component of non-canonical Wnt signaling, and its dysregulation causes colorectal cancer metastasis. Dysregulated expression of CCDC88C was observed in lymph node metastatic tumor tissues of breast cancer. However, the role of CCDC88C in breast cancer metastasis remains unclear. To address this, the stable BT549 and SKBR3 cell lines with CCDC88C overexpression or knockdown were developed. Loss/gain-of-function experiments suggested that CCDC88C drove breast cancer cell motility in vitro and lung and liver metastasis in vivo. We found that CCDC88C led to c-JUN-induced transcription activation. Overlapping genes were identified from the genes modulated by CCDC88C and c-JUN. CEMIP, one of these overlapping genes, has been confirmed to confer breast cancer metastasis. We found that CCDC88C regulated CEMIP mRNA levels via c-JUN and it exerted pro-metastatic capabilities in a CEMIP-dependent manner. Moreover, we identified the CCDC88C as a substrate of polypeptide N-acetylgalactosaminyltransferase 6 (GALNT6). GALNT6 was positively correlated with CCDC88C protein abundance in the normal breast and breast cancer tissues, indicating that GALNT6 might be associated with expression patterns of CCDC88C in breast cancer. Our data demonstrated that GALNT6 maintained CCDC88C stability by promoting its O-linked glycosylation, and the modification was critical for the pro-metastatic potential of CCDC88C. CCDC88C also could mediate the pro-metastatic potential of GALNT6 in breast cancer. Collectively, our findings uncover that CCDC88C may increase the risk of breast cancer metastasis and elucidate the underlying molecular mechanisms.© 2024. The Author(s).