Clin Mol Hepatol.
2024 Oct;30(4):895-913. 10.3350/cmh.2024.0364.
KCTD17-mediated Ras stabilization promotes hepatocellular carcinoma progression
- Jung YH1,2,3
- Lee YJ1,2,3
- Dao T4
- Jung KH1,3
- Yu J5,6
- Oh AR1,2,3
- Jeong Y1,2,3
- Gi H1,2,3
- Kim YU1,2,3
- Ryu D4
- Carrer M7
- Pajvani UB5
- Lee SB
8 - Hong SS1,2,3
- Kim K1,2,3
- Affiliations
-
- 1Department of Biomedical Sciences, College of Medicine, College of Medicine, Inha University, Incheon, Korea
- 2Program in Biomedical Science & Engineering, College of Medicine, Inha University, Incheon, Korea
- 3Research Center for Controlling Intercellular Communication (RCIC), College of Medicine, Inha University, Incheon, Korea
- 4Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju, Korea
- 5Department of Medicine, Columbia University, New York, NY, USA
- 6Institute of Pharmaceutical Sciences, China Pharmaceutical University, Nanjing, China
- 7Ionis Pharmaceuticals Inc., Carlsbad, CA, USA
- 8Division of Life Sciences, Jeonbuk National University, Jeonju, Korea
- KMID: 2560092
- DOI: http://doi.org/10.3350/cmh.2024.0364
Abstract
- Background/Aims
Potassium channel tetramerization domain containing 17 (KCTD17) protein, an adaptor for the cullin3 (Cul3) ubiquitin ligase complex, has been implicated in various human diseases; however, its role in hepatocellular carcinoma (HCC) remains elusive. Here, we aimed to elucidate the clinical features of KCTD17, and investigate the mechanisms by which KCTD17 affects HCC progression.
Methods
We analyzed transcriptomic data from patients with HCC. Hepatocyte-specific KCTD17 deficient mice were treated with diethylnitrosamine (DEN) to assess its effect on HCC progression. Additionally, we tested KCTD17-directed antisense oligonucleotides for their therapeutic potential in vivo.
Results
Our investigation revealed the upregulation of KCTD17 expression in both tumors from patients with HCC and mouse models of HCC, in comparison to non-tumor controls. We identified the leucine zipper-like transcriptional regulator 1 (Lztr1) protein, a previously identified Ras destabilizer, as a substrate for KCTD17-Cul3 complex. KCTD17-mediated Lztr1 degradation led to Ras stabilization, resulting in increased proliferation, migration, and wound healing in liver cancer cells. Hepatocyte-specific KCTD17 deficient mice or liver cancer xenograft models were less susceptible to carcinogenesis or tumor growth. Similarly, treatment with KCTD17-directed antisense oligonucleotides (ASO) in a mouse model of HCC markedly lowered tumor volume as well as Ras protein levels, compared to those in control ASO-treated mice.
Conclusions
KCTD17 induces the stabilization of Ras and downstream signaling pathways and HCC progression and may represent a novel therapeutic target for HCC.
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