[PubMed] [Google Scholar] 50. cells through its transcriptional activation.21, 22, 23 Open in a separate window Figure 1 A, Among 51 ABC transporters, ABCB1 is a representative transporter that enhances outward efflux activity of anticancer drugs from the inside to the outside of cancer cells, resulting in acquired multidrug resistance. Enhanced transcriptional activation of is first presented as a transcriptional mechanism of how tumor multidrug resistance is acquired during chemotherapeutic treatments in various human malignancies. also induces activation of various other resistance\related genes, including MVP/LRPPCNAMYCTOP2ACD44CD49fp53BCL2and poor outcomes in ovarian tumors. To date, based on expression levels of YBX1 in cancer cells, when assessed using IHC or qRT\PCR, almost all 70 independent studies have consistently shown a close relationship between enhanced expression of YBX1 and poor outcomes in over 20 human tumor types (Table?1, Doc S1). Enhanced nuclear/cytoplasmic expression of YBX1 is negatively associated with overall survival or disease\free survival in patients with various malignancies. In particular, nuclear YBX1 expression in cancer cells is significantly associated with poor outcomes in various malignancies, including breast, ovary, prostate, colon, liver, lung, bone, soft tissue, thyroid, skin, and nervous system, as well as osteosarcomas and hematological tumors (Table?1, Doc S1). In addition, enhanced expression of YBX1 is positively correlated with various biomarkers, including MVP/LRPEGFRHER2ARFGFR2and the top 500 genes that are negatively correlated with estrogen receptor 1 (and the top 500 genes that are negatively correlated with YBX1. Several representative genes are presented YBX1 expression is also negatively correlated with ER expression in breast cancer cells in?vitro and in?vivo.36, 47 Expression levels of mRNA are inversely correlated with expression levels of or estrogen receptor 1 (and negatively correlated with (Figure?3E).37, 51 Therefore, the enhanced expression of YBX1 is reciprocally associated with reduced expression of various ER\targeted genes, indicating that YBX1 preferentially promotes ER\independent tumor growth and survival. The findings suggest that YBX1 has oncogenic potential in breast cancer and that YBX1 could be a therapeutic target in breast cancer refractory to endocrine therapeutics. 5.?PHOSPHORYLATION AND NUCLEAR LOCALIZATION OF YBX1 ARE REQUIRED FOR ITS ONCOGENIC DRIVER FUNCTIONS Nuclear localization of YBX1 predicts poor outcomes in patients with various cancers (Table?1, LNP023 Doc S1). Therefore, future studies should investigate the mechanisms by which YBX1 in the nucleus functions as an oncogenic transcription factor for various effector genes associated with malignant progression. Figure?4A presents representative images of phosphorylated YBX1 (pYBX1 Ser102) in the nucleus of cancer cells in malignantly progressive tumors from patients. Phosphorylation of YBX1 at Ser102 is essential for its nuclear translocation in cancer cells. YBX1 Ser102 phosphorylation is suppressed by inhibitors of PI3K, mTORC1, and p90 ribosomal S6 kinase (RSK).29, 52, 53, 54 Figure?4B shows the suppression of nuclear localization by a PI3K inhibitor (LY294002) or an mTORC1 inhibitor (everolimus). Consistent with Figure?4B, an Ser102 phosphorylation\null mutant construct of YBX1 could not be translocated into the nucleus, which was accompanied by downregulated expression of EGFR and HER2, in breast cancer cells.52 Therefore, various kinases involved in AKT/mTOR and MEK/ERK signaling pathways influence both the phosphorylation and nuclear translocation of YBX1 (Figure?4C). Open in a separate window Figure 4 A, Representative immunohistochemistry images of expression of phosphorylated Y\box binding protein\1 (pYBX1) with an antibody recognizing.Potential role for YB\1 in castration\resistant prostate cancer and resistance to enzalutamide through the androgen receptor V7. mechanism of ABCB1 overexpression, transcriptional activation of is most often reported in various human malignancies and in cancer cell lines (Figure?1A). Y\box binding protein\1 (YBX1) binds to the Y\box sequence in the 5\flanking region of in drug\resistant cancer cells to promote its transcriptional activation (Figure?1A,B).10, 11, 12, 13 In addition, YBX1 binds to the Y\box sequence in many other drug resistance\related genes (Figure?1B).11, 14, 15, 16, 17, 18, 19, 20 Therefore, YBX1 drives the acquisition of drug resistance in cancer cells through its transcriptional activation.21, 22, 23 Open in a separate window Figure 1 A, Among 51 ABC transporters, ABCB1 is a representative transporter that enhances outward efflux activity of anticancer drugs from the inside LNP023 to the outside of cancer cells, resulting in acquired multidrug resistance. Enhanced transcriptional activation of is first presented as a transcriptional mechanism of how tumor multidrug resistance is acquired during chemotherapeutic treatments in various human malignancies. also induces activation of various other resistance\related genes, including MVP/LRPPCNAMYCTOP2ACD44CD49fp53BCL2and poor outcomes in ovarian tumors. To date, based on expression levels of YBX1 in cancer cells, when assessed using IHC or qRT\PCR, almost all 70 independent studies have consistently shown a close relationship between enhanced expression of YBX1 and poor outcomes in over 20 human tumor types (Table?1, Doc S1). Enhanced nuclear/cytoplasmic expression of YBX1 is negatively associated with overall survival or disease\free survival in patients with various malignancies. In particular, nuclear YBX1 expression in cancer cells is significantly associated with poor outcomes in various malignancies, including breast, ovary, prostate, colon, liver, lung, bone, soft tissue, thyroid, skin, and nervous system, as well as osteosarcomas and hematological tumors (Table?1, Doc S1). In addition, enhanced expression of YBX1 is positively correlated with various biomarkers, including MVP/LRPEGFRHER2ARFGFR2and the top 500 genes that are negatively correlated with estrogen receptor 1 (and the top 500 genes that are negatively correlated with YBX1. Several representative genes are presented YBX1 expression is also negatively correlated with ER expression in breast cancer cells in?vitro and in?vivo.36, 47 Expression levels of mRNA are inversely correlated with expression levels of or estrogen receptor 1 (and negatively correlated with (Figure?3E).37, 51 Therefore, the enhanced expression of YBX1 is reciprocally associated with reduced expression of various ER\targeted genes, indicating that YBX1 preferentially promotes ER\independent tumor growth and survival. The findings suggest that YBX1 has oncogenic potential in breast cancer and that YBX1 could be a therapeutic target in breast cancer refractory to endocrine therapeutics. 5.?PHOSPHORYLATION AND NUCLEAR LOCALIZATION OF YBX1 ARE REQUIRED FOR ITS ONCOGENIC DRIVER FUNCTIONS Nuclear localization of YBX1 predicts poor outcomes in patients with various cancers (Table?1, Doc S1). Therefore, future studies should investigate the mechanisms by which YBX1 in the nucleus functions as an oncogenic transcription factor for various effector genes associated with malignant progression. Figure?4A presents representative images of phosphorylated YBX1 (pYBX1 Ser102) in the nucleus of cancer cells in malignantly progressive tumors from patients. Phosphorylation of YBX1 at Ser102 is essential for its nuclear translocation in cancer cells. YBX1 Ser102 phosphorylation is suppressed by inhibitors of PI3K, mTORC1, and p90 ribosomal S6 kinase (RSK).29, 52, 53, 54 Figure?4B shows the suppression LNP023 of nuclear localization by a PI3K inhibitor (LY294002) or an mTORC1 inhibitor (everolimus). Consistent with Figure?4B, an Ser102 phosphorylation\null mutant construct of YBX1 could not be translocated into the nucleus, which was accompanied by downregulated expression of EGFR and HER2, in breast cancer cells.52 Therefore, various kinases involved in AKT/mTOR and MEK/ERK signaling pathways influence both the phosphorylation and nuclear translocation of YBX1 (Number?4C). Open in a separate window Number 4 A, Representative immunohistochemistry images of manifestation of phosphorylated Y\package binding protein\1 (pYBX1) with an antibody realizing pYBX1 Ser102 in breast cancer cells. pYBX1 is definitely preferentially localized in the nucleus of malignancy cells in individuals with progressive tumor. Left panel shows the bad control. B, Inhibitors of both PI3K/AKT (LY294002) and mTORC1 (everolimus) suppress nuclear localization of YBX1 in malignancy cells. C, Hypothetical model of how YBX1 is definitely activated through its phosphorylation at Ser102. YBX1 is definitely phosphorylated and triggered by PI3K/AKT/mTORC1 and/or MEK/ERK signaling pathways, advertising nuclear translocation 6.?TARGETING YBX1 CONTRIBUTES TO Even Rabbit Polyclonal to PFKFB1/4 more DEVELOPMENT OF EFFECTIVE ANTICANCER THERAPEUTICS Preclinical therapeutic studies focusing on YBX1 itself have been assessed. A.
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