Glucocorticoid promotes metastasis of colorectal cancer via co-regulation of glucocorticoid receptor and TET2 (RNA-Seq)
Background  Glucocorticoids (GCs), commonly used for anti-inflammatory and cancer treatments, have been linked to the promotion of cancer metastasis. Yet, the molecular mechanisms behind this potential remain poorly understood. Clarifying these mechanisms is crucial for a nuanced understanding and potential refinement of GC therapies in the context of cancer treatment. Methods  In HEK293T cells, co-immunoprecipitation (Co-IP) and chromatin immunoprecipation sequencing (ChIP-seq) were used with antibodies of GR and TET family proteins (TET1, TET2, TET3). Drup repositioning was performed through the LINCS database, using common genes of GR and TET2 in HEK293 and HCT116 cell lines with CRC differentially expressed genes (DEGs). Cell migration and invasion were tested in colorectal cancer (CRC) cell lines with varying glucocorticoid receptor (GR) expression, i.e., HCT116 and HT29 cell lines.  Findings  Dexamethasone (Dex) treatment resulted in a significant difference in cell migration rates in two CRC cell lines with disparate GR expression levels. Co-IP and ChIP-seq analyses substantiated the interaction between GR and TET family proteins in HEK293T cells. Belinostat, the selected compound, was successfully validated for its potential to counteract the effects of GC-induced inversion in CRC cells in vitro. Transcriptomic analyses of Belinostat-treated HCT116 cells revealed down-regulation of target genes associated with cancer metastasis..  Interpretation This study provides valuable insights into the molecular mechanisms underlying GC-induced metastasis, introducing newly repositioned compounds that could serve as potential adjuvant therapy to GC treatment. Furthermore, it opens avenues for exploring novel drug candidates for CRC treatment. Overall design: RNA-seq was performed to investigate cell migration situation with GC. We established two colorectal cancer (CRC) cell lines with varying glucocorticoid receptor (GR) expression (HCT116 and HT29). We then investigate cell invasion with two drugs (Dex and belinostat) treated in CRC cells (HCT116 and HT29).