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Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs
Published on: May 15, 2019
βTrCP1 promotes SLC35F2 protein ubiquitination and inhibits cancer progression in HeLa cells
Jencia Carminha Colaco1, Arun Pandian Chandrasekaran1, Janardhan Keshav Karapurkar1
1Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, 04763, South Korea.
Abstract:
The solute carrier family 35 F2 (SLC35F2) belongs to membrane-bound carrier proteins that are associated with multiple cancers. The main factor that determines cancer progression is the expression level of SLC35F2. Thus, identifying the E3 ligase that controls SLC35F2 protein abundance in cancer cells is critical. Here, we identified βTrCP1 interacting with and reducing the SLC35F2 protein level. βTrCP1 signals SLC35F2 protein ubiquitination and reduces SLC35F2 protein half-life. The mRNA expression pattern between βTrCP1 and SLC35F2 across a panel of cancer cell lines showed a negative correlation. Additionally, the depletion of βTrCP1 accumulated SLC35F2 protein and promoted SLC35F2-mediated cell growth, migration, invasion, and colony formation ability in HeLa cells. Overall, we demonstrate that βTrCP1 acts as a tumor suppressor by controlling SLC35F2 protein abundance in cancer cells. The depletion of βTrCP1 promotes SLC35F2-mediated carcinogenesis. Thus, we envision that βTrCP1 may be a potential target for cancer therapeutics.
Insights
Beta-transducin repeat-containing protein 1 (βTrCP1) targets solute carrier family 35 F2 (SLC35F2) for degradation, acting as a tumor suppressor. Depleting βTrCP1 enhances SLC35F2 levels and promotes cancer progression.
Area of Science:
- Molecular biology
- Cancer research
- Biochemistry
Background:
- Solute carrier family 35 F2 (SLC35F2) is implicated in cancer progression.
- Understanding SLC35F2 regulation is crucial for cancer therapy.
Purpose of the Study:
- To identify the E3 ligase responsible for SLC35F2 protein degradation.
- To investigate the role of βTrCP1 in regulating SLC35F2 levels and cancer cell behavior.
Main Methods:
- Co-immunoprecipitation to identify interacting proteins.
- Western blotting to assess protein levels and half-life.
- Cellular assays to evaluate cell growth, migration, invasion, and colony formation.
Main Results:
- Beta-transducin repeat-containing protein 1 (βTrCP1) directly interacts with and ubiquitinates SLC35F2, reducing its protein half-life.
- A negative correlation was observed between βTrCP1 and SLC35F2 mRNA expression in cancer cell lines.
- βTrCP1 depletion led to SLC35F2 accumulation and enhanced cancer cell phenotypes (growth, migration, invasion, colony formation).
Conclusions:
- βTrCP1 functions as a tumor suppressor by degrading SLC35F2.
- βTrCP1 depletion promotes SLC35F2-mediated carcinogenesis.
- βTrCP1 represents a potential therapeutic target for cancers involving SLC35F2.
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