CRISPR/Cas9-Mediated TERT Disruption in Cancer Cells

• Main Authors: Luan Wen, Changzhi Zhao, Jun Song, Linyuan Ma, Jinxue Ruan, Xiaofeng Xia, Y. Eugene Chen, Jifeng Zhang, Peter X. Ma, Jie Xu
• Format: Article
• Language: English
• Published: MDPI AG 2020-01-01
• Series: International Journal of Molecular Sciences
• Subjects: crispr/cas9; gene editing; telomerase; tert; cancer therapy
• Online Access: https://www.mdpi.com/1422-0067/21/2/653

Mammalian telomere lengths are primarily regulated by telomerase, a ribonucleoprotein consisting of a reverse transcriptase (TERT) and an RNA subunit (TERC). TERC is constitutively expressed in all cells, whereas TERT expression is temporally and spatially regulated, such that in most adult somatic cells, TERT is inactivated and telomerase activity is undetectable. Most tumor cells activate TERT as a mechanism for preventing progressive telomere attrition to achieve proliferative immortality. Therefore, inactivating TERT has been considered to be a promising means of cancer therapy. Here we applied the CRISPR/Cas9 gene editing system to target the TERT gene in cancer cells. We report that disruption of TERT severely compromises cancer cell survival in vitro and in vivo. Haploinsufficiency of TERT in tumor cells is sufficient to result in telomere attrition and growth retardation in vitro. In vivo, TERT haploinsufficient tumor cells failed to form xenograft after transplantation to nude mice. Our work demonstrates that gene editing-mediated TERT knockout is a potential therapeutic option for treating cancer.