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Theranostics 2020; 10(14):6095-6112. doi:10.7150/thno.44147 This issue Cite

Research Paper

Harnessing stemness and PD-L1 expression by AT-rich interaction domain-containing protein 3B in colorectal cancer

Tsai-Tsen Liao1,2, Chun-Chi Lin3,4,5, Jeng-Kae Jiang4,5, Shung-Haur Yang4,6, Hao-Wei Teng4,8, Muh-Hwa Yang3,7,8✉

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

✉ Corresponding author: Muh-Hwa Yang, Institute of Clinical Medicine, National Yang-Ming University, No. 155, Sec. 2, Li-Nong Street, Taipei 112, Taiwan. E-mail: mhyang2gov.tw, Tel.: 886-228267000, ext. 7911, Fax: 886-228235870

Citation:
Liao TT, Lin CC, Jiang JK, Yang SH, Teng HW, Yang MH. Harnessing stemness and PD-L1 expression by AT-rich interaction domain-containing protein 3B in colorectal cancer. Theranostics 2020; 10(14):6095-6112. doi:10.7150/thno.44147. https://www.thno.org/v10p6095.htm
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Abstract

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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

Citation styles

APA
Liao, T.T., Lin, C.C., Jiang, J.K., Yang, S.H., Teng, H.W., Yang, M.H. (2020). Harnessing stemness and PD-L1 expression by AT-rich interaction domain-containing protein 3B in colorectal cancer. Theranostics, 10(14), 6095-6112. https://doi.org/10.7150/thno.44147.

ACS
Liao, T.T.; Lin, C.C.; Jiang, J.K.; Yang, S.H.; Teng, H.W.; Yang, M.H. Harnessing stemness and PD-L1 expression by AT-rich interaction domain-containing protein 3B in colorectal cancer. Theranostics 2020, 10 (14), 6095-6112. DOI: 10.7150/thno.44147.

NLM
Liao TT, Lin CC, Jiang JK, Yang SH, Teng HW, Yang MH. Harnessing stemness and PD-L1 expression by AT-rich interaction domain-containing protein 3B in colorectal cancer. Theranostics 2020; 10(14):6095-6112. doi:10.7150/thno.44147. https://www.thno.org/v10p6095.htm

CSE
Liao TT, Lin CC, Jiang JK, Yang SH, Teng HW, Yang MH. 2020. Harnessing stemness and PD-L1 expression by AT-rich interaction domain-containing protein 3B in colorectal cancer. Theranostics. 10(14):6095-6112.

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