Cystatin E/M (CST6), a representative cysteine protease inhibitor, plays both tumor-promoting and tumor-suppressing functions and is pursued as an epigenetically therapeutic target in special cancer types. However, a comprehensive and systematic analysis for CST6 in pan-cancer level is still lacking. In the present study, we explored the expression pattern of CST6 in multiple cancer types across ∼10,000 samples from TCGA (The Cancer Genome Atlas) and ∼8,000 samples from MMDs (Merged Microarray-acquired Datasets). We found that the dynamic expression alteration of CST6 was consistent with dual function in different types of cancer. In addition, we observed that the expression of CST6 was globally regulated by the DNA methylation in its promoter region. CST6 expression was positively correlated with the epithelial cell infiltration involved in epithelial-to-mesenchymal transition (EMT) and proliferation. The relationship between CST6 and tumor microenvironment was also explored. In particular, we found that CST6 serves a protective function in the process of melanoma metastasis. Finally, the clinical association analysis further revealed the dual function of CST6 in cancer, and a combination of the epithelial cell infiltration and CST6 expression could predict the prognosis for SKCM patients. In summary, this first CST6 pan-cancer study improves the understanding of the dual functional effects on CST6 in different types of human cancer.

Cystatin E/M (CST6) 是一种代表性的半胱氨酸蛋白酶抑制剂，兼具促癌和抑癌功能，被作为特殊癌症类型的表观遗传学治疗靶点。然而，目前仍缺乏对泛癌水平的 CST6 的全面系统分析。在本研究中，我们探索了 CST6 在来自 TCGA（癌症基因组图谱）的约 10,000 个样本和来自 MMD（合并微阵列获得的数据集）的约 8,000 个样本的多种癌症类型中的表达模式。我们发现 CST6 的动态表达改变与不同类型癌症中的双重功能一致。此外，我们观察到 CST6 的表达受到其启动子区域 DNA 甲基化的全局调控。CST6 表达与涉及上皮间质转化 (EMT) 和增殖的上皮细胞浸润呈正相关。还探讨了 CST6 与肿瘤微环境之间的关系。特别是，我们发现 CST6 在黑色素瘤转移过程中起到保护作用。最后，临床关联分析进一步揭示了 CST6 在癌症中的双重功能，结合上皮细胞浸润和 CST6 表达可以预测 SKCM 患者的预后。总之，这项第一个 CST6 泛癌研究提高了对 CST6 在不同类型人类癌症中的双重功能影响的理解。我们发现 CST6 在黑色素瘤转移过程中起到保护作用。最后，临床关联分析进一步揭示了 CST6 在癌症中的双重功能，结合上皮细胞浸润和 CST6 表达可以预测 SKCM 患者的预后。总之，这项第一个 CST6 泛癌研究提高了对 CST6 在不同类型人类癌症中的双重功能影响的理解。我们发现 CST6 在黑色素瘤转移过程中起到保护作用。最后，临床关联分析进一步揭示了 CST6 在癌症中的双重功能，结合上皮细胞浸润和 CST6 表达可以预测 SKCM 患者的预后。总之，这项第一个 CST6 泛癌研究提高了对 CST6 在不同类型人类癌症中的双重功能影响的理解。