Network Inference Analysis Identifies SETDB1 as a Key Regulator for Reverting Colorectal Cancer Cells into Differentiated Normal-Like Cells
| Autor: | Younghyun Han, Kwang-Hyun Cho, Seok-Hyung Kim, Dongsan Kim, Chansu Lee, Soobeom Lee, Chae Young Hwang, Sung Noh Hong |
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| Rok vydání: | 2019 |
| Předmět: |
Cancer Research
Colorectal cancer Cellular differentiation Gene regulatory network Biology Transfection 03 medical and health sciences Histone H3 0302 clinical medicine Cell Line Tumor medicine Tumor Cells Cultured Humans Gene Regulatory Networks CDX2 Molecular Biology Embryonic Stem Cells 030304 developmental biology 0303 health sciences Cell Differentiation Histone-Lysine N-Methyltransferase medicine.disease HCT116 Cells Embryonic stem cell Gene Expression Regulation Neoplastic Oncology 030220 oncology & carcinogenesis Cancer cell Cancer research Neoplastic Stem Cells Stem cell Caco-2 Cells Colorectal Neoplasms |
| Zdroj: | Molecular cancer research : MCR. 18(1) |
| ISSN: | 1557-3125 |
| Popis: | Cancer cells exhibit properties of cells in a less differentiated state than the adjacent normal cells in the tissue. We explored whether cancer cells can be converted to a differentiated normal-like state by restoring the gene regulatory network (GRN) of normal cells. Here, we report that colorectal cancer cells exhibit a range of developmental states from embryonic and intestinal stem-like cells to differentiated normal-like cells. To identify the transcription factors (TF) that commit stem-like colorectal cancer cells into a differentiated normal-like state, we reconstructed GRNs of normal colon mucosa and identified core TFs (CDX2, ELF3, HNF4G, PPARG, and VDR) that govern the cellular state. We further found that SET Domain Bifurcated 1 (SETDB1), a histone H3 lysine 9–specific methyltransferase, hinders the function of the identified TFs. SETDB1 depletion effectively converts stem-like colorectal cancer cells into postmitotic cells and restores normal morphology in patient-derived colorectal cancer organoids. RNA-sequencing analyses revealed that SETDB1 depletion recapitulates global gene expression profiles of normal differentiated cells by restoring the transcriptional activity of core TFs on their target genes. Implications: Our study provides insights into the molecular regulatory mechanism underlying the developmental hierarchy of colorectal cancer and suggests that induction of a postmitotic state may be a therapeutic alternative to destruction of cancer cells. |
| Databáze: | OpenAIRE |
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