The role of ubiquitin-specific protease 10 (USP10) as modulator of the hypoxia and EGF response in colon cancer

Thesis event information

Date and time of the thesis defence

Place of the thesis defence

F101, Aapistie 7

Topic of the dissertation

The role of ubiquitin-specific protease 10 (USP10) as modulator of the hypoxia and EGF response in colon cancer

Doctoral candidate

Master of Science Kateryna Kubaichuk

Faculty and unit

University of Oulu Graduate School, Faculty of Biochemistry and Molecular Medicine, ECM and Hypoxia

Subject of study

Biochemistry and molecular biology

Opponent

Professor Carsten Scholz, University Medicine Greifswald, Institute of Physiology, Germany

Custos

Professor Thomas Kietzmann, University of Oulu

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The role of ubiquitin-specific protease 10 (USP10) as modulator of the hypoxia and EGF response in colon cancer

Colorectal cancer ranks among the third most common human malignant diseases and is one of the leading causes of cancer-related deaths globally. Cancer cells display a disturbed protein homeostasis which affects the function of several signaling pathways such as the epidermal growth factor receptor (EGFR) and the hypoxia response. Ubiquitin-ligase initiated proteasomal degradation as well as its prevention by deubiquitinases (DUBs) are supposed to contribute to the above-mentioned disturbances.
Treatment for colon cancer usually involves surgery, radiation therapy, chemo- and immune as well as targeted therapy with EGFR tyrosine kinase inhibitors or antibodies. However, it has become apparent that a high number of colorectal cancer patients develop resistance to anti-EGFR therapy.
The EGFR signaling cascade is known to be dependent on several modifications such as phosphorylation and ubiquitylation as well as to affect the hypoxia response. While EGFR´s action via phosphorylation has been well characterized, not much is known about the involvement of its ubiquitinating and deubiquitinating enzymes and their effect on the hypoxia response.
The DUB ubiquitin-specific protease 10 (USP10) was proposed to be an important player in the control of colon cancer cell viability and my thus represent an interesting player being able to modify EGFR signaling and the hypoxia response.
In this study we investigated the role of USP10 in colon cancer by employing different cellular models with USP10 knockout, and xenotransplants in nude mice. The current study has shown that loss of USP10 in colon cancer cells promotes proliferation, migration and colony formation and reduces adhesion. This is accompanied by increases in HIF-1α levels and a changed energy phenotype of the cells. Lack of USP10 was further accompanied by a reduced sensitivity towards the EGFR tyrosine kinase inhibiting drug gefitinib as well as a reduced activation of ERK1/2 MAP kinases and AKT1/PKB when cells were stimulated with EGF. Interestingly, it appeared that these phenomena were partially mediated by the two proteins sortilin/NTR3 and INPP4B. Furthermore, in-vivo xenograft transplantation experiments with USP10 deficient cells in nude mice corroborated the important role of USP10 in conjunction with sortilin/NTR3 and INPP4B during carcinogenesis.
Altogether, these findings suggest that USP10 is able to participate in colon carcinogenesis by modulating the hypoxia response and the EGFR signaling pathway and may represent a therapeutic target.
Last updated: 8.12.2022