Department of Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai City, 200233, China.
Department of Internal Medicine, Huzhou Traditional Chinese Medicine Hospital Affiliated to Zhejiang Chinese Medical University, Huzhou City, Zhejiang Province, 313000, China.
Cell Death Dis. 2021 Oct 12;12(10):930. doi: 10.1038/s41419-021-04185-7.
Colorectal tumorigenesis is a heterogeneous disease driven by multiple genetic and epigenetic alterations. F-box and WD repeat domain containing 11 (FBXW11) is a member of the F-box protein family that regulates the ubiquitination of key factors associated with tumor growth and aggressiveness. Our study aimed to explore the role of FBXW11 in the development and metastasis of colorectal cancer (CRC). FBXW11 was overexpressed in colorectal tumor tissues and its overexpression was associated with a poor prognosis of CRC patients. The upregulation of FBXW11 not only promoted cell proliferation, invasion, and migration, but also contributed to maintaining stem-cell features in colorectal tumor cells. Further analysis revealed that FBXW11 targeted hypermethylated in cancer 1 (HIC1) and reduced its stability in CRC cells through ubiquitination. Moreover, the expression of sirtuin 1 (SIRT1), a deacetylase in tumor cells was upregulated by FBXW11 via regulating HIC1 expression. The mouse xenograft models of CRC confirmed that FBXW11 knockdown impeded colorectal tumor growth and liver metastasis in vivo. In summary, our study identified FBXW11 as an oncogenic factor that contributed to stem-cell-like properties and liver metastasis in CRC via regulating HIC1-mediated SIRT1 expression. These results provide a rationale for the development of FBXW11-targeting drugs for CRC patients.
结直肠肿瘤发生是一种由多种遗传和表观遗传改变驱动的异质性疾病。F-box 和 WD 重复域蛋白 11（FBXW11）是 F-box 蛋白家族的一员，可调节与肿瘤生长和侵袭性相关的关键因子的泛素化。我们的研究旨在探讨 FBXW11 在结直肠癌（CRC）发生和转移中的作用。FBXW11 在结直肠肿瘤组织中过表达，其过表达与 CRC 患者的预后不良相关。FBXW11 的上调不仅促进了细胞增殖、侵袭和迁移，而且有助于维持结直肠肿瘤细胞的干细胞特征。进一步的分析表明，FBXW11 通过泛素化靶向癌症中高甲基化 1（HIC1）并降低其在 CRC 细胞中的稳定性。此外，FBXW11 通过调节 HIC1 表达上调肿瘤细胞中的去乙酰化酶 SIRT1 的表达。CRC 的小鼠异种移植模型证实，FBXW11 敲低可阻碍体内结直肠肿瘤的生长和肝转移。总之，我们的研究确定 FBXW11 是一种癌基因因子，通过调节 HIC1 介导的 SIRT1 表达，促进 CRC 中的干细胞样特性和肝转移。这些结果为开发针对 CRC 患者的 FBXW11 靶向药物提供了依据。
