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Oncogenic Y-box binding protein-1 as an effective therapeutic target in drug-resistant cancer
Michihiko Kuwano1, Tomohiro Shibata2, Kosuke Watari2
1Cancer Translational Research Center, St. Mary's Institute of Health Sciences, Kurume, Japan.
Abstract:
Y-box binding protein-1 (YBX1), a multifunctional oncoprotein containing an evolutionarily conserved cold shock domain, dysregulates a wide range of genes involved in cell proliferation and survival, drug resistance, and chromatin destabilization by cancer. Expression of a multidrug resistance-associated ATP binding cassette transporter gene, ABCB1, as well as growth factor receptor genes, EGFR and HER2/ErbB2, was initially discovered to be transcriptionally activated by YBX1 in cancer cells. Expression of other drug resistance-related genes, MVP/LRP, TOP2A, CD44, CD49f, BCL2, MYC, and androgen receptor (AR), is also transcriptionally activated by YBX1, consistently indicating that YBX1 is involved in tumor drug resistance. Furthermore, there is strong evidence to support that nuclear localization and/or overexpression of YBX1 can predict poor outcomes in patients with more than 20 different tumor types. YBX1 is phosphorylated by kinases, including AKT, p70S6K, and p90RSK, and translocated into the nucleus to promote the transcription of resistance- and malignancy-related genes. Phosphorylated YBX1, therefore, plays a crucial role as a potent transcription factor in cancer. Herein, a novel anticancer therapeutic strategy is presented by targeting activated YBX1 to overcome drug resistance and malignant progression.
Insights
Y-box binding protein-1 (YBX1) drives cancer progression and drug resistance by activating key genes. Targeting activated YBX1 offers a novel strategy to combat cancer
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Y-box binding protein-1 (YBX1) is an oncoprotein that regulates genes critical for cancer cell proliferation, survival, and drug resistance.
- YBX1 activates genes such as ABCB1, EGFR, HER2/ErbB2, and others involved in multidrug resistance and tumor progression.
- Overexpression or nuclear localization of YBX1 correlates with poor patient outcomes across diverse cancer types.
Purpose of the Study:
- To investigate the role of YBX1 as a transcription factor in cancer malignancy and drug resistance.
- To present a novel therapeutic strategy targeting activated YBX1 for cancer treatment.
Main Methods:
- The study reviews existing evidence on YBX1's transcriptional activity and its role in cancer.
- Investigated the phosphorylation of YBX1 by kinases like AKT, p70S6K, and p90RSK.
- Examined the nuclear translocation of phosphorylated YBX1 and its downstream effects.
Main Results:
- YBX1 transcriptionally activates numerous genes implicated in cancer drug resistance, including ABCB1, MVP/LRP, TOP2A, CD44, CD49f, BCL2, MYC, and androgen receptor (AR).
- Phosphorylation by specific kinases leads to YBX1 nuclear translocation, enhancing the transcription of malignancy-related genes.
- Activated YBX1 functions as a potent transcription factor in cancer.
Conclusions:
- YBX1 plays a significant role in promoting tumor drug resistance and malignant progression.
- Targeting activated YBX1 represents a promising therapeutic avenue to overcome cancer drug resistance and improve patient outcomes.
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