Cancer-keeper genes as therapeutic targets

Xizhe Zhang; Chunyu Pan; Xinru Wei; Meng Yu; Shuangjie Liu; Jun An; Jieping Yang; Baojun Wei; Wenjun Hao; Yang Yao; Yuyan Zhu; Weixiong Zhang

doi:10.1016/j.isci.2023.107296

Cancer-keeper genes as therapeutic targets

iScience. 2023 Jul 11;26(8):107296. doi: 10.1016/j.isci.2023.107296. eCollection 2023 Aug 18.

Authors

Xizhe Zhang^{1

2}, Chunyu Pan³, Xinru Wei^{1

2}, Meng Yu^{4

5}, Shuangjie Liu⁶, Jun An⁶, Jieping Yang⁶, Baojun Wei⁶, Wenjun Hao⁶, Yang Yao⁷, Yuyan Zhu⁶, Weixiong Zhang^{8

9}

Affiliations

¹ Early Intervention Unit, Department of Psychiatry, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing, China.
² School of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing, China.
³ School of Computer Science and Engineering, Northeastern University, Shenyang, China.
⁴ Department of Laboratory Animal Science, China Medical University, Shenyang, China.
⁵ Key Laboratory of Transgenetic Animal Research, China Medical University, Shenyang, China.
⁶ Department of Urology, First Affiliated Hospital of China Medical University, Shenyang, China.
⁷ Department of Physiology, Shenyang Medical College, Shenyang, China.
⁸ Department of Health Technology and Informatics, Department of Computing, The Hong Kong Polytechnic University, Hong Kong, China.
⁹ Department of Computer Science and Engineering, Department of Genetics, Washington University in St. Louis, St. Louis, MO, USA.

Abstract

Finding cancer-driver genes has been a central theme of cancer research. We took a different perspective; instead of considering normal cells, we focused on cancerous cells and genes that maintained abnormal cell growth, which we named cancer-keeper genes (CKGs). Intervening CKGs may rectify aberrant cell growth, making them potential cancer therapeutic targets. We introduced control-hub genes and developed an efficient algorithm by extending network controllability theory. Control hub are essential for maintaining cancerous states and thus can be taken as CKGs. We applied our CKG-based approach to bladder cancer (BLCA). All genes on the cell-cycle and p53 pathways in BLCA were identified as CKGs, showing their importance in cancer. We discovered that sensitive CKGs - genes easily altered by structural perturbation - were particularly suitable therapeutic targets. Experiments on cell lines and a mouse model confirmed that six sensitive CKGs effectively suppressed cancer cell growth, demonstrating the immense therapeutic potential of CKGs.

Keywords: Cancer; Drugs; Therapeutics.