Theranostics 2020; 10(14):6095-6112. doi:10.7150/thno.44147 This issue Cite
1. Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
2. Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University
3. Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
4. School of Medicine, National Yang-Ming University, Taipei, Taiwan
5. Division of Colorectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan
6. Department of Surgery, National Yang-Ming University Hospital, I-Lan, Taiwan
7. Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan
8. Cancer Progression Research Center, National Yang-Ming University, Taipei, Taiwan
Background and Aims: Cancer stem cells (CSCs) have been shown to be responsible for the tumor initiation, metastasis, and therapeutic resistance of colorectal cancer (CRC). Recent studies have also indicated the importance of CSCs in escaping immune surveillance. However, the coordinated epigenetic control of the stem cell signature and the key molecule(s) involved in immunosurveillance of colorectal CSCs (CRCSCs) are unclear. Here, we investigated the role of a histone modifier, AT-rich interaction domain-containing protein 3B (ARID3B), in CRC.
Methods: CRC patient-derived xenografts (PDXs) with knockout of ARID3B induced by CRISPR/Cas9 in vivo were used. Molecular/cellular biology assays were performed. Clinical data obtained from The Cancer Genome Atlas, as well as from our cohort (Taipei Veterans General Hospital), were analyzed.
Results: ARID3B was crucial for the growth of CRC, and ARID3B promoted the stem-like features of CRC. Mechanistically, ARID3B activated Notch target genes, intestinal stem cell (ISC) genes, and programmed death-ligand 1 (PD-L1) through the recruitment of lysine-specific demethylase 4C (KDM4C) to modulate the chromatin configuration for transcriptional activation. Clinical sample analyses showed that the coexpression of ARID3B and the Notch target HES1 correlated with a worse outcome and that ARID3B and PD-L1 were highly expressed in the consensus molecular subtype 4 of CRC. Pharmacological inhibition of KDM4 activity reversed the ARID3B-induced signature.
Conclusion: We reveal a noncanonical Notch pathway for activating Notch target genes, ISC genes, and PD-L1 in CRC. This finding explains the immune escape of CRCSCs and indicates a potential group that may benefit from immune checkpoint inhibitors. Epigenetic drugs for reversing stem-like features of CRC should also be investigated.
Keywords: ARID3B, cancer stem cell, colorectal cancer, Notch, programmed death ligand 1