1. KCTD17-mediated Ras stabilization promotes hepatocellular carcinoma progression
- Author
-
Young Hoon Jung, Yun Ji Lee, Tam Dao, Kyung Hee Jung, Junjie Yu, Ah-Reum Oh, Yelin Jeong, HyunJoon Gi, Young Un Kim, Dongryeol Ryu, Michele Carrer, Utpal B. Pajvani, Sang Bae Lee, Soon-Sun Hong, and KyeongJin Kim
- Subjects
hcc ,kctd17 ,ras ,lztr1 ,antisense oligonucleotides ,Diseases of the digestive system. Gastroenterology ,RC799-869 - 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.
- Published
- 2024
- Full Text
- View/download PDF