Skp2 Stabilizes Mcl-1 and Confers Radioresistance in Colorectal Cancer

Authors

Xinfang Yu
Li Zhou
Wenbin Liu
Lijun Liu
Feng Gao
Wei Li
Haidan Liu

Publication Date

3-18-2022

Journal

Cell Death & Disease

DOI

10.1038/s41419-022-04685-0

PMID

35301297

PMCID

PMC8930992

PubMedCentral® Posted Date

3-18-2022

PubMedCentral® Full Text Version

Post-Print

Published Open-Access

yes

Keywords

Carcinogenesis, Cell Line, Tumor, Colorectal Neoplasms, Humans, Myeloid Cell Leukemia Sequence 1 Protein, S-Phase Kinase-Associated Proteins, Ubiquitin-Protein Ligases, Ubiquitination, Biological sciences, Ubiquitylation

Abstract

Overexpression of Skp2 plays a critical role in tumorigenesis and correlates with poor prognosis in human malignancies. Thus, Skp2 has been proposed as an attractive target for anti-tumor interventions. The expression of Skp2 in human colorectal cancer (CRC) and the role of Skp2 in tumorigenic properties and irradiation sensitivities of CRC cells were examined by anchorage-dependent and -independent growth assays, immunoblot, flow cytometry, immunohistochemical staining, ubiquitination analysis, co-immunoprecipitation assay, CRISPR-Cas9-based gene knockout, and xenograft experiments. Skp2 is highly expressed in CRC patient tissues. Blocking Skp2 expression reduces the tumorigenic properties of CRC cells in vitro and in vivo. Depletion of Skp2 confers sensitivity to irradiation of CRC cells. Skp2 deficiency enhances irradiation-induced intrinsic apoptosis by facilitating E3 ligase FBW7-mediated Mcl-1 ubiquitination and degradation. Knockout of Skp2 sensitizes CRC cells to irradiation treatments in vivo. Our findings indicate that Skp2 stabilizes Mcl-1, and targeting Skp2 in combination with traditional radiotherapy might be efficacious in treating CRC.

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