Tumor-initiating cells (TICs) maintain heterogeneity within tumors and seed metastases at distant sites, contributing to therapeutic resistance and disease recurrence. In colorectal cancer (CRC), strategy that effectively eradicates TICs and is of potential value for clinical use still remains in need.
Methods
: The anti-tumorigenic activity of a small-molecule inhibitor of KDM6 histone demethylases named GSK-J4 in CRC was evaluated by
in vitro
assays and
in vivo
imaging of xenografted tumors. Sphere formation, flow cytometry analysis of cell surface markers and intestinal organoid formation were performed to examine the impact of GSK-J4 on TIC properties. Transcriptome analysis and global profiling of H3K27ac, H3K27me3, and KDM6A levels by ChIP-seq were conducted to elucidate how KDM6 inhibition reshapes epigenetic landscape and thereby eliminating TICs.
Results
: GSK-J4 alleviated the malignant phenotypes of CRC cells
in vitro
and
in vivo
, sensitized them to chemotherapeutic treatment, and strongly repressed TIC properties and stemness-associated gene signatures in these cells. Mechanistically, KDM6 inhibition induced global enhancer reprogramming with a preferential impact on super-enhancer-associated genes, including some key genes that control stemness in CRC such as
ID1
. Besides, expression of both Kdm6a and Kdm6b was more abundant in mouse intestinal crypt when compared with upper villus and inhibition of their activities blocked intestinal organoid formation. Finally, we unveiled the power of KDM6B in predicting both the overall survival outcome and recurrence of CRC patients.
Conclusions
: Our study provides a novel rational strategy to eradicate TICs through reshaping epigenetic landscape in CRC, which might also be beneficial for optimizing current therapeutics.
We have recently demonstrated that tau hyperphosphorylation causes diabetic synaptic neurodegeneration of retinal ganglion cells (RGCs), which might be the earliest affair during the pathogenesis of diabetic retinopathy (DR). Thus, there is a pressing need to seek therapeutic agents possessing neuroprotective effects against tau hyperphosphorylation in RGCs for arresting the progression of DR. Here, using a well-characterized diabetes model of db/db mouse, we discovered that topical ocular application of 10 mg/kg/day of ginsenoside Rg1 (GRg1), one of the major active ingredients extracted from Panax ginseng and Panax notoginseng, ameliorated hyperphosphorylated tau-triggered RGCs synaptic neurodegeneration in diabetic mice. The neuroprotective effects of GRg1 on diabetic retinae were abrogated when retinal IRS-1 or Akt was suppressed by intravitreal injection with si-IRS-1 or topically coadministered with a specific inhibitor of Akt, respectively. However, selective repression of retinal GSK3β by intravitreal administration of si-GSK3β rescued the neuroprotective properties of GRg1 when Akt was inactivated. Therefore, the present study showed for the first time that GRg1 can prevent hyperphosphorylated tauinduced synaptic neurodegeneration of RGCs via activation of IRS-1/Akt/GSK3β signaling in the early phase of DR. Moreover, our data clarify the potential therapeutic significance of GRg1 for neuroprotective intervention strategies of DR.
Significance
This study uncovered the role of ZNF280C, a known DNA damage response protein, as a tumorigenic transcription regulator that contributes to colorectal tumorigenesis and metastasis through maintaining an epigenetic repression program at key cancer gene loci. These findings identified a contributor with potential prognostic value to colorectal pathogenesis and provide mechanistic insight to the essential function of transcription factor in fine-tuning the activity of chromatin regulators for proper transcription control.
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