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FIBP knockdown attenuates growth and enhances chemotherapy in colorectal cancer via regulating GSK3?-related pathways.

ABSTRACT: Colorectal cancer stem cells (CSCs), characterized by self-renewal ability and high expression of proliferative genes, contribute to the chemoresistance of colorectal cancer (CRC). We aimed to identify the molecular mechanisms underlying CRC chemoresistance through comprehensive bioinformatics screenings and experimental confirmation of gene functions. We found that high expression of FGF1 intracellular binding protein (FIBP) was correlated with chemoresistance and poor prognosis in CRC patients. Therefore, the chemoresistant CRC cell line HCT116-CSC with high expression of the stem cell markers CD44 and CD133 was established for further phenotypic tests. FIBP knockdown inhibited proliferation, enhanced chemotherapy effects, and attenuated the stemness markers of CRC cells in vivo and in vitro. Through RNA-seq and gene set enrichment analysis, we identified cyclin D1 as a key downstream target in FIBP-regulated cell cycle progression and proliferation. Moreover, FIBP bound to GSK3?, inhibited its phosphorylation at Tyr216, and activated ?-catenin/TCF/cyclin D1 signaling in HCT116-CSCs. Additional GSK3? knockdown reversed the FIBP silencing-induced inhibition of proliferation and decreased stemness marker expression in HCT116-CSCs. Furthermore, DNA methylation profiling suggested that FIBP regulated the stemness of CRC cells via methylation activity that was dependent on GSK3? but independent of ?-catenin signaling. Our data illuminate the potential of FIBP as a novel therapeutic target for treating chemoresistant CRC through inhibition of GSK3?-related signaling.

SUBMITTER: Huang YF

PROVIDER: S-EPMC6167373 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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FIBP knockdown attenuates growth and enhances chemotherapy in colorectal cancer via regulating GSK3β-related pathways.

Huang Yan-Feng YF Niu Wen-Bo WB Hu Rong R Wang Ling-Jun LJ Huang Zeng-Yan ZY Ni Shi-Hao SH Wang Ming-Qing MQ Yang Yi Y Huang Yu-Sheng YS Feng Wen-Jun WJ Xiao Wei W Zhu Da-Jian DJ Xian Shao-Xiang SX Lu Lu L

Oncogenesis 20181002 9

Colorectal cancer stem cells (CSCs), characterized by self-renewal ability and high expression of proliferative genes, contribute to the chemoresistance of colorectal cancer (CRC). We aimed to identify the molecular mechanisms underlying CRC chemoresistance through comprehensive bioinformatics screenings and experimental confirmation of gene functions. We found that high expression of FGF1 intracellular binding protein (FIBP) was correlated with chemoresistance and poor prognosis in CRC patients ...[more]

PMID: 30275459

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Project description:Glioblastoma (GBM) is the most commonly diagnosed brain tumor that exhibit high mortality rate and chemotherapy resistance is a major clinical problem. Recent studies suggest that estrogen receptor beta (ERβ), may function as a tumor suppressor in GBM. However, the mechanism(s) by which ERβ contributes to GBM suppression and chemotherapy response remains unknown. We examined the role of ERβ in the DNA damage response of GBM cells, and tested whether ERβ sensitizes GBM cells to chemotherapy. Cell viability and survival assays using multiple epitope tagged ERβ expressing established and primary GBM cells demonstrated that ERβ sensitizes GBM cells to DNA damaging agents including temozolomide (TMZ). RNA-seq studies using ERβ overexpression models revealed downregulation of number of genes involved in DNA recombination and repair, ATM signaling and cell cycle check point control. Gene set enrichment analysis (GSEA) suggested that ERβ-modulated genes were correlated negatively with homologous recombination, mismatch repair and G2M checkpoint genes. Further, RT-qPCR analysis revealed that chemotherapy induced activation of cell cycle arrest and apoptosis genes were attenuated in ERβKO cells. Additionally, ERβ overexpressing cells had a higher number of γH2AX foci following TMZ treatment. Mechanistic studies showed that ERβ plays an important role in homologous recombination (HR) mediated repair and ERβ reduced expression and activation of ATM upon DNA damage. More importantly, GBM cells expressing ERβ had increased survival when compared to control GBM cells in orthotopic GBM models. ERβ overexpression further enhanced the survival of mice to TMZ therapy in both TMZ sensitive and TMZ resistant GBM models. Additionally, IHC analysis revealed that ERβ tumors had increased expression of γH2AX and cleaved caspase-3. Using ERβ-overexpression and ERβ-KO GBM model cells, we have provided the evidence that ERβ is required for optimal chemotherapy induced DNA damage response and apoptosis in GBM cells.

Dataset Information

FIBP knockdown attenuates growth and enhances chemotherapy in colorectal cancer via regulating GSK3?-related pathways.

Publications

FIBP knockdown attenuates growth and enhances chemotherapy in colorectal cancer via regulating GSK3β-related pathways.

Similar Datasets

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