Abstract
Simple SummaryNCOR1 is a scaffold protein that interacts with multiple partners to repress gene transcription. NCOR1 controls immunometabolic functions in several tissues and has been recently shown to protect against experimental colitis in mice. Our laboratory has observed a pro-proliferative role of NCOR1 in normal intestinal epithelial cells. However, it is unclear whether NCOR1 is functionally involved in colon cancer. This study demonstrated that NCOR1 is required for colorectal cancer cell growth. Depletion of NCOR1 caused these cells to become senescent. Transcriptomic signatures confirmed these observations but also predicted the potential for these cells to become pro-invasive. Thus, NCOR1 plays a novel role in preventing cancer-associated senescence and could represent a target for controlling colon cancer progression.NCOR1 is a corepressor that mediates transcriptional repression through its association with nuclear receptors and specific transcription factors. Some evidence supports a role for NCOR1 in neonatal intestinal epithelium maturation and the maintenance of epithelial integrity during experimental colitis in mice. We hypothesized that NCOR1 could control colorectal cancer cell proliferation and tumorigenicity. Conditional intestinal epithelial deletion of Ncor1 in ApcMin/+ mice resulted in a significant reduction in polyposis. RNAi targeting of NCOR1 in Caco-2/15 and HT-29 cell lines led to a reduction in cell growth, characterized by cellular senescence associated with a secretory phenotype. Tumor growth of HT-29 cells was reduced in the absence of NCOR1 in the mouse xenografts. RNA-seq transcriptome profiling of colon cancer cells confirmed the senescence phenotype in the absence of NCOR1 and predicted the occurrence of a pro-migration cellular signature in this context. SOX2, a transcription factor essential for pluripotency of embryonic stem cells, was induced under these conditions. In conclusion, depletion of NCOR1 reduced intestinal polyposis in mice and caused growth arrest, leading to senescence in human colorectal cell lines. The acquisition of a pro-metastasis signature in the absence of NCOR1 could indicate long-term potential adverse consequences of colon-cancer-induced senescence.
Highlights
NCOR1 was originally discovered as a protein interactor of thyroid hormone receptors (TR) and retinoic acid receptors (RAR), which repressed the transcription of genes harboring these DNA elements [1,2]
The loss of one Ncor1 allele in the intestinal epithelium led to a 29.3% reduction in polyp load in the ApcMin/+ background (p < 0.05) and a 41.3% reduction when both Ncor1 alleles were lost under the same background (p < 0.001) (Figure 1B)
To further validate some of the targets associated with signaling cellular pathways as listed above, we investigated their gene transcript expression profiles following the knockdown of NCOR1 expression in both Caco-2/15 and HT-29 cells after 3 and 7 days, following introduction of shRNA constructs
Summary
NCOR1 (nuclear corepressor 1) was originally discovered as a protein interactor of thyroid hormone receptors (TR) and retinoic acid receptors (RAR), which repressed the transcription of genes harboring these DNA elements [1,2]. It was further discovered that the transcriptional repressive function of NCOR1 extended beyond interactions with nuclear receptors. NCOR1 can interact with c-Jun and be recruited to AP1 sites on target gene promoters [3]. Additional proteins of the complex are involved in sensing signals to mediate chromatin corepressor exchange via the action of specific kinases and ubiquitylases [6]. NCOR1 functions as a large protein platform complex that integrates multiple regulatory proteins involved in epigenetic modifications, leading to chromatin compaction and gene repression
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