The Skp2 Pathway: A Critical Target for Cancer Therapy

Zhen Cai; Asad Moten; Danni Peng; Che-Chia Hsu; Bo-Syong Pan; Rajeshkumar Manne; Hong-Yu Li; Hui-Kuan Lin

doi:10.1016/j.semcancer.2020.01.013

The Skp2 Pathway: A Critical Target for Cancer Therapy

Semin Cancer Biol. 2020 Dec;67(Pt 2):16-33. doi: 10.1016/j.semcancer.2020.01.013. Epub 2020 Feb 1.

Authors

Zhen Cai¹, Asad Moten², Danni Peng³, Che-Chia Hsu³, Bo-Syong Pan³, Rajeshkumar Manne³, Hong-Yu Li⁴, Hui-Kuan Lin⁵

Affiliations

¹ Department of Cancer Biology, Wake Forest Baptist Medical Center, Wake Forest University, Winston Salem, NC, 27101, USA. Electronic address: zcai@wakehealth.edu.
² National Capital Consortium, Department of Defense, Washington DC, 20307, USA; Institute for Complex Systems, HealthNovations International, Houston, TX, 77089, USA; Center for Cancer Research, National Institutes of Health, Bethesda, MD, 20814, USA; Center on Genomics, Vulnerable Populations, and Health Disparities, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02115, USA.
³ Department of Cancer Biology, Wake Forest Baptist Medical Center, Wake Forest University, Winston Salem, NC, 27101, USA.
⁴ University of Arkansas for Medical Sciences, College of Pharmacy, Division of Pharmaceutical Science, 200 South Cedar, Little Rock AR 72202, USA.
⁵ Department of Cancer Biology, Wake Forest Baptist Medical Center, Wake Forest University, Winston Salem, NC, 27101, USA; Graduate Institute of Basic Medical Science, China Medical University, Taichung 404, Taiwan; Department of Biotechnology, Asia University, Taichung 41354, Taiwan. Electronic address: hulin@wakehealth.edu.

Abstract

Strictly regulated protein degradation by ubiquitin-proteasome system (UPS) is essential for various cellular processes whose dysregulation is linked to serious diseases including cancer. Skp2, a well characterized component of Skp2-SCF E3 ligase complex, is able to conjugate both K48-linked ubiquitin chains and K63-linked ubiquitin chains on its diverse substrates, inducing proteasome mediated proteolysis or modulating the function of tagged substrates respectively. Overexpression of Skp2 is observed in various human cancers associated with poor survival and adverse therapeutic outcomes, which in turn suggests that Skp2 engages in tumorigenic activity. To that end, the oncogenic properties of Skp2 are demonstrated by various genetic mouse models, highlighting the potential of Skp2 as a target for tackling cancer. In this article, we will describe the downstream substrates of Skp2 as well as upstream regulators for Skp2-SCF complex activity. We will further summarize the comprehensive oncogenic functions of Skp2 while describing diverse strategies and therapeutic platforms currently available for developing Skp2 inhibitors.

Keywords: Skp2-SCF complex; cancer targeting; ubiquitination.

Publication types

Research Support, N.I.H., Extramural
Review

MeSH terms

Animals
Carcinogens
Drug Resistance, Neoplasm / genetics*
Female
Gene Expression Regulation
Humans
Male
Metabolic Networks and Pathways
Mice
Molecular Targeted Therapy / methods*
Neoplasms / drug therapy
Neoplasms / genetics
Neoplasms / pathology*
S-Phase Kinase-Associated Proteins / genetics
S-Phase Kinase-Associated Proteins / metabolism*
Ubiquitination

Substances

Carcinogens
S-Phase Kinase-Associated Proteins
SKP2 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding