The Skp2 Pathway: A Critical Target for Cancer Therapy.
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2020-12
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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.
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Cai, Zhen, Asad Moten, Danni Peng, Che-Chia Hsu, Bo-Syong Pan, Rajeshkumar Manne, Hong-Yu Li, Hui-Kuan Lin, et al. (2020). The Skp2 Pathway: A Critical Target for Cancer Therapy. Seminars in cancer biology, 67(Pt 2). pp. 16–33. 10.1016/j.semcancer.2020.01.013 Retrieved from https://hdl.handle.net/10161/31156.
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Scholars@Duke
Che-Chia Hsu
My research has focused on mitochondrial functions in cancer metabolism and understand the role of mitochondrial dynamics in cellular function and human diseases including cancers. Additionally, I also continuously dissect cancer metabolism and identifying potential metabolic vulnerabilities of cancer initiation, progression and metastasis using several in vitro, ex vivo and in vivo genetical approaches such as CRISPR/Cas9 knockout, mouse/ human organoid cultures and genetically engineered mouse models, thereby characterizing molecular mechanisms regulated by metabolic pathways and developing potential metabolic interventions for targeting cancers.
RAJESHKUMAR MANNE
Hui-Kuan Lin
The research interest in Dr. Lin lab is to understand oncogenic networks between oncogenes and tumor suppressor genes, dissect the regulatory mechanisms underlying the crosstalk between ageing and cancer, to unravel the role of posttranslational modifications (PTMs) such as ubiquitination and metabolism in diverse molecular and biological processes important for cancer progression and metastasis, cancer stem regulation, cancer immunity and drug resistance by using biochemical and molecular approaches along with and genetic mouse models, and finally to develop small molecule inhibitors and antibodies targeting critical oncogenic signaling and metabolic vulnerabilities for cancer treatment. His research goals aim to not only reveal fundamental insights and concepts for cancer biology and cancer immunity, but also develop novel paradigms and therapeutic strategies for targeting human cancer and overcoming drug resistance.
Research interests include:
- Crosstalk between oncogenic and tumor suppressor networks
- Posttranslational modifications in signaling and cancer
- Cancer progression and metastasis
- Biology of normal and cancer stem cells
- Metabolism in cancer and ageing
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