Oncogenic Y‐box binding protein‐1 as an effective therapeutic target in drug‐resistant cancer

• Published in: Cancer science 2019-05, Vol.110 (5), p.1536-1543
• Main Authors: Kuwano, Michihiko, Shibata, Tomohiro, Watari, Kosuke, Ono, Mayumi
• Format: Article
• Language: English
• Subjects: ABC transporters; AKT protein; Androgen receptors; Androgens; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Binding sites; Cancer; Cancer therapies; CD44 antigen; Cell cycle; Cell growth; Cell Nucleus - metabolism; Cell proliferation; Cell survival; Chromatin; Cold shock proteins; Cytoplasm; Cytotoxicity; Drug delivery systems; Drug resistance; Drug Resistance, Neoplasm - drug effects; Epidermal growth factor; Epidermal growth factor receptors; ErbB-2 protein; Female; Gene amplification; Gene Expression Regulation, Neoplastic - drug effects; Gene Regulatory Networks; Humans; Kinases; Localization; Male; Malignancy; malignant progression; Medical research; Molecular Targeted Therapy; Multidrug resistance; Myc protein; Neoplasms - drug therapy; Neoplasms - metabolism; oncogenic effector; overcoming drug resistance; Phosphorylation; Phosphorylation - drug effects; Prognosis; Proteins; Review; Therapeutic applications; Transcription factors; Transcriptional Activation; Tumors; Y-Box-Binding Protein 1 - metabolism; Y‐box binding protein‐1
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.14006

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. The oncogenic Y‐box binding protein‐1, YBX1, is a DNA/RNA binding multifunctional protein and YBX1 has recently been highlighted as a compelling therapeutic target. Enhanced expression of YBX1 in the nucleus and/or cytoplasm of cancer cells can also predict poor outcomes in more than 20 different tumor types including breast, lung, ovarian, prostate, and others. Furthermore, various research groups have recently started to develop novel and potent therapeutic drugs against progressive cancers by targeting YBX1.