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Theranostics 2020; 10(13):5845-5864. doi:10.7150/thno.44043 This issue Cite

Research Paper

Small-molecule activating SIRT6 elicits therapeutic effects and synergistically promotes anti-tumor activity of vitamin D3 in colorectal cancer

Jialin Shang1,*, Zhehui Zhu2,*, Yingyi Chen1,*, Jinglue Song2, Yuji Huang2, Kun Song1, Jie Zhong1, Xinyuan Xu1, Jiacheng Wei1, Chengxiang Wang1, Long Cui2, Chen-Ying Liu2,✉, Jian Zhang1,3,4,✉

1. State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao-Tong University School of Medicine, Shanghai 200025, China.
2. Department of Colorectal and Anal Surgery, Xinhua Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai 200092, China.
3. Medicinal Bioinformatics Center, Shanghai Jiao-Tong University School of Medicine, Shanghai 200025, China.
4. School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China.
*These authors contributed equally to this work.

✉ Corresponding authors: Dr. Jian Zhang, Ph.D. Phone: +86-21-63846590-776922; Fax: +86-21-64154900; E-mail: jian.zhangedu.cn. Dr. Chen-Ying Liu, Ph.D. Phone: +86-21-25077492; Fax: +86-21-25077492; E-mail: liuchenyingcom.cn

Citation:
Shang J, Zhu Z, Chen Y, Song J, Huang Y, Song K, Zhong J, Xu X, Wei J, Wang C, Cui L, Liu CY, Zhang J. Small-molecule activating SIRT6 elicits therapeutic effects and synergistically promotes anti-tumor activity of vitamin D3 in colorectal cancer. Theranostics 2020; 10(13):5845-5864. doi:10.7150/thno.44043. https://www.thno.org/v10p5845.htm
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Abstract

Graphic abstract

Colorectal cancer (CRC) is the leading cause of cancer death; however, targets with broad anti-CRC effects are limited. Sirtuin6 (SIRT6) is a conserved nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase that is widely pathologically downregulated in CRC, but its pharmacological effect in CRC remains undefined due to the lack of small-molecule SIRT6 activators. We searched for a compound activating SIRT6 and investigated its anti-CRC effect in various models.

Methods: We identified an allosteric SIRT6 activator, MDL-811. Its ability to enhance SIRT6 deacetylation at protein and cellular levels was evaluated by Fluor de Lys (FDL) and western blots. We assessed the proliferation of 26 CRC cell lines and patient-derived organoids (PDOs) treated with MDL-811. In vivo efficacy of MDL-811 was evaluated in HCT116 cell line- and patient-derived xenografts as well as a spontaneous CRC model. RNA sequencing and real-time quantitative PCR assays were performed to analyze gene expression changes in MDL-811-treated HCT116 cells. Along with controls in SIRT6-overexpressing HCT116 cells, the SIRT6-mediated histone H3 deacetylation at the Cytochrome P450 family 24 subfamily A member 1 (CYP24A1) gene locus was assessed by chromatin immunoprecipitation (ChIP) in MDL-811-treated HCT116 cells. A combination therapy against CRC based on the downstream gene of SIRT6 activation was evaluated in cells and mouse models.

Results: MDL-811 significantly activated SIRT6 histone H3 deacetylation (H3K9Ac, H3K18Ac, and H3K56Ac) in vitro and had broad antiproliferative effects on diverse CRC cell lines and PDOs. More importantly, the in vivo anti-tumor efficacy of MDL-811 was demonstrated across cell line- and patient-derived xenografts and in the APCmin/+ spontaneous CRC model. Mechanically, we identified a new downstream target gene of SIRT6 in CRC, CYP24A1. Based on these findings, a combination drug strategy with MDL-811 to synergistically enhance the anti-CRC effect of vitamin D3 was validated in vitro and in vivo.

Conclusions: Our data provide proof of concept that targeting SIRT6 using a small-molecule activator is an attractive therapeutic strategy for CRC and that MDL-811 could be a promising lead compound for further preclinical and clinical studies of treatments for CRC.

Keywords: Colorectal cancer, Translational medicine, SIRT6 activator, CYP24A1, Vitamin D3

Citation styles

APA
Shang, J., Zhu, Z., Chen, Y., Song, J., Huang, Y., Song, K., Zhong, J., Xu, X., Wei, J., Wang, C., Cui, L., Liu, C.Y., Zhang, J. (2020). Small-molecule activating SIRT6 elicits therapeutic effects and synergistically promotes anti-tumor activity of vitamin D3 in colorectal cancer. Theranostics, 10(13), 5845-5864. https://doi.org/10.7150/thno.44043.

ACS
Shang, J.; Zhu, Z.; Chen, Y.; Song, J.; Huang, Y.; Song, K.; Zhong, J.; Xu, X.; Wei, J.; Wang, C.; Cui, L.; Liu, C.Y.; Zhang, J. Small-molecule activating SIRT6 elicits therapeutic effects and synergistically promotes anti-tumor activity of vitamin D3 in colorectal cancer. Theranostics 2020, 10 (13), 5845-5864. DOI: 10.7150/thno.44043.

NLM
Shang J, Zhu Z, Chen Y, Song J, Huang Y, Song K, Zhong J, Xu X, Wei J, Wang C, Cui L, Liu CY, Zhang J. Small-molecule activating SIRT6 elicits therapeutic effects and synergistically promotes anti-tumor activity of vitamin D3 in colorectal cancer. Theranostics 2020; 10(13):5845-5864. doi:10.7150/thno.44043. https://www.thno.org/v10p5845.htm

CSE
Shang J, Zhu Z, Chen Y, Song J, Huang Y, Song K, Zhong J, Xu X, Wei J, Wang C, Cui L, Liu CY, Zhang J. 2020. Small-molecule activating SIRT6 elicits therapeutic effects and synergistically promotes anti-tumor activity of vitamin D3 in colorectal cancer. Theranostics. 10(13):5845-5864.

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