Besides its role in more common cancer types described above, YBX1 has also been shown to play a role in virus-induced cancers. Human papillomaviruses are implicated in cervical cancers and also in a subtype of head and neck cancers. Leiprecht et al found that YBX1 plays a critical role in papillomavirus-induced tumor formation by interacting with the viral regulatory protein E2, leading to increased expression of important oncogenes in rabbit keratinocyte cell lines.Collectively, the accumulated evidence supports the critical role of YBX1 in cancer development in both non-virus and virus-induced cancers.
The multi-faceted effects of YBX1 in cancer are also reflected by its important role in cancer chemotherapy drug resistance.Elevated levels of YBX1 have been associated with resistance to chemotherapy drugs in different types of cancers. This is a great challenge to clinicians, as it limits their ability to control disease progression and to improve patient survival. Various studies have highlighted novel factors that can be targeted to reduce YBX1-based drug resistance. For instance, YBX1 plays an important role in the chemotherapy drug taxane's resistance in ovarian cancer cells. It is reported that the focal adhesion kinase (FAK), a non-receptor tyrosine kinase that usually promotes cell growth, is involved in the regulation of YBX1-dependent drug resistance.Inhibition of FAK causes increased sensitivity to taxane by decreasing YBX1 phosphorylation and YBX1 nuclear accumulation in an Akt-dependent manner. In addition to taxane resistance, expression of YBX1 is also shown to confer resistance to cisplatin treatment in ovarian cancer cells.
In addition to chemotherapy drug resistance, YBX1 also plays an important role in stress-induced drug resistance. One such important drug resistance gene regulated by YBX1 is the multi-drug resistance 1 (MDR1) gene. MDR1 has Y box in its promoter region. It was observed that during environmental stress, YBX1 caused the increased expression of MDR1, leading to environmental stress-dependent drug resistance. Basaki et al showed that Akt-mediated nuclear translocation of YBX1 is important for acquiring drug resistance through upregulation of MDR1 in human ovarian cancer cells. Knockdown of YBX1 also resulted in increased sensitization to DNA-damaging agents and ionizing radiation, thus suggesting it might exert protective effects against cytotoxic DNA-damaging agents in human colon cancer cells.Therefore, certain functions of YBX1, like managing the stress response, can also contribute to drug resistance in response to environmental factors.
Taken together, YBX1 plays an essential and unique role in cancer progression, chemotherapy drug resistance, and environmental factors related to its cytoprotective effects.