FBXW11 contributes to stem-cell-like features and liver metastasis through regulating HIC1-mediated SIRT1 transcription in colorectal cancer

Jing Yao,Jun Yang,Xin-Ping Wang,Zhe Yang,Tong Yang,Bing Ji,Zheng-Yun Zhang

doi:10.1038/s41419-021-04185-7

Abstract

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.

Highlights

Colorectal cancer (CRC) is a lethal malignancy worldwide with nearly 900,000 deaths per year [1]
F-box and WD repeat domain containing 11 (FBXW11) is upregulated in CRC tissues To explore whether FBXW11 was involved in the progression of CRC, we first analyzed the mRNA expression of FBXW11 in 145 pairs of colorectal tumor tissues and paired non-tumorous tissues
Similar to other malignancies, liver metastasis is the major cause of cancer-related mortality in CRC, which occurs in ~50% of all cases [24]

Summary

Introduction

Colorectal cancer (CRC) is a lethal malignancy worldwide with nearly 900,000 deaths per year [1]. The age-standardized incidence of CRC is 19.7 per 100,000 people, making it the third most common carcinoma in both men and women [2]. Due to the growing aging population and increasing dietary fat intake in recent decades, the prevalence of CRC has been elevating rapidly in Asian countries, including China [3]. Intratumor heterogeneity is a hallmark of CRC and has been considered a major problem limiting the efficacy of current therapies [5]. Cancer stem cells (CSCs) represent a subgroup of cells within a tumor that are phenotypically and functionally heterogeneous and highly dynamic [6]. Therapeutic strategies targeting stem-cell-like features in tumor cells may present a promising approach for CRC patients

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Conclusion