KCTD17-mediated Ras stabilization promotes hepatocellular carcinoma progression
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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.
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.
참고문헌 (52)
- Niu ZS, "Genetic alterations in hepatocellular carcinoma : an update", World J Gastroenterol, 22, pp.9069~9095 (2016)
- Zhou J, "Guidelines for diagnosis and treatment of primary liver cancer in China(2017 edition)", Liver Cancer, 7, pp.235~260 (2018)
- Lepage C, "Survival in patients with primary liver cancer, gallbladder and extrahepatic biliary tract cancer and pancreatic cancer in Europe 1999-2007 : results of EUROCARE-5", Eur J Cancer, 51, pp.2169~2178 (2015)
- Siegel RL, "Cancer statistics, 2018", CA Cancer J Clin, 68, pp.7~30 (2018)
- Zhu AX, "Effect of everolimus on survival in advanced hepatocellular carcinoma after failure of sorafenib : the EVOLVE-1 randomized clinical trial", JAMA, 312, pp.57~67 (2014)
- Llovet JM, "Molecular therapies and precision medicine for hepatocellular carcinoma", Nat Rev Clin Oncol, 15, pp.599~616 (2018)
- Marisi G, "Ten years of sorafenib in hepatocellular carcinoma : are there any predictive and", or prognostic markers?, 2018, pp.24, 4152~4163
- Personeni N, "Lenvatinib for the treatment of unresectable hepatocellular carcinoma : evidence to date", J Hepatocell Carcinoma, 6, pp.31~39 (2019)
- Vogel A, "Correction to : "Hepatocellular carcinoma : ESMO Clinical Practice Guidelines for diagnosis, treatment and followup"", Ann Oncol, 30, pp.871~873 (2019)
- Abou-Alfa GK, "Cabozantinib in patients with advanced and progressing hepatocellular carcinoma", N Engl J Med, 379, pp.54~63 (2018)
- Bruix J, "Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment(RESORCE) : a randomised, double-blind, placebo-controlled, phase 3 trial", Lancet, 389, pp.56~66 (2017)
- De Luca E, "Ramucirumab, a second-line option for patients with hepatocellular carcinoma : a review of the evidence", Cancer Manag Res, 12, pp.3721~3729 (2020)
- Teng X, "KCTD : a new gene family involved in neurodevelopmental and neuropsychiatric disorders", CNS Neurosci Ther, 25, pp.887~902 (2019)
- Ji AX, "Structural insights into KCTD protein assembly and Cullin3recognition", J Mol Biol, 428, pp.92~107 (2016)
- Pinkas DM, "Structural complexity in the KCTD family of Cullin3-dependent E3 ubiquitin ligases", Biochem J, 474, pp.3747~3761 (2017)
- Skoblov M, "Protein partners of KCTD proteins provide insights about their functional roles in cell differentiation and vertebrate development", Bioessays, 35, pp.586~596 (2013)
- Kim K, "Degradation of PHLPP2 by KCTD17, via a glucagondependent pathway, promotes hepatic steatosis", Gastroenterology, 153, pp.1568~1580 (2017)
- Oh AR, "Hepatocyte Kctd17 inhibition ameliorates glucose intolerance and hepatic steatosis caused by obesity-induced Chrebp stabilization", Gastroenterology, 164, pp.439~453 (2023)
- Sanyal A, "Populationbased risk factors and resource utilization for HCC : US perspective", Curr Med Res Opin, 26, pp.2183~2191 (2010)
- Baffy G, "Hepatocellular carcinoma in non-alcoholic fatty liver disease : an emerging menace", J Hepatol, 56, pp.1384~1391 (2012)
- Wong RJ, "Nonalcoholic steatohepatitis is the most rapidly growing indication for liver transplantation in patients with hepatocellular carcinoma in the U. S", Hepatology, 59, pp.2188~2195 (2014)
- Abe T, "LZTR1facilitates polyubiquitination and degradation of RAS-GTPases", Cell Death Differ, 27, pp.1023~1035 (2020)
- Bigenzahn JW, "LZTR1 is a regulator of RAS ubiquitination and signaling", Science, 362, pp.1171~1177 (2018)
- Steklov M, "Mutations in LZTR1 drive human disease by dysregulating RAS ubiquitination", Science, 362, pp.1177~1182 (2018)
- Yu G, "clusterProfiler : an R package for comparing biological themes among gene clusters", OMICS, 16, pp.284~287 (2012)
- Platt RJ, "CRISPR-Cas9 knockin mice for genome editing and cancer modeling", Cell, 159, pp.440~455 (2014)
- Li S, "Pioglitazone reduces hepatocellular carcinoma development in two rodent models of cirrhosis", J Gastrointest Surg, 23, pp.101~111 (2019)
- Ho C, "AKT(v-akt murine thymoma viral oncogene homolog 1)and N-Ras(neuroblastoma ras viral oncogene homolog)coactivation in the mouse liver promotes rapid carcinogenesis by way of mTOR(mammalian target of rapamycin complex 1), FOXM1(forkhead box M1)", SKP2, and c-Myc pathways, 2012, pp.55, 833~845
- Stauffer JK, "Coactivation of AKT and β-catenin in mice rapidly induces formation of lipogenic liver tumors", Cancer Res, 71, pp.2718~2727 (2011)
- Zhu C, "Notch activity characterizes a common hepatocellular carcinoma subtype with unique molecular and clinicopathologic features", J Hepatol, 74, pp.613~626 (2021)
- Shin MC, "Kctd17-mediated Chop degradation promotes adipogenic differentiation", Biochem Biophys Res Commun, 653, pp.126~132 (2023)
- Vasquez G, "Site-specific incorporation of 5’-methyl DNA enhances the therapeutic profile of gapmer ASOs", Nucleic Acids Res, 49, pp.1828~1839 (2021)
- Llovet JM, "Sorafenib in advanced hepatocellular carcinoma", N Engl J Med, 359, pp.378~390 (2008)
- Kalyan A, "Systemic therapy of hepatocellular carcinoma : current and promising", Clin Liver Dis, 19, pp.421~432 (2015)
- Zenker M, "Noonan syndrome : improving recognition and diagnosis", Arch Dis Child, 107, pp.1073~1078 (2022)
- The Cancer Genome Atlas Research Network, "Comprehensive and integrative genomic characterization of hepatocellular carcinoma", Cell, 169, pp.1327~1341 (2017)
- Yi T, "LncRNA LL22NC03-N14H11. 1 promoted hepatocellular carcinoma progression through activating MAPK pathway to induce mitochondrial fission", Cell Death Dis, 11, pp.832~ (2020)
- Liu YT, "A novel spontaneous hepatocellular carcinoma mouse model for studying T-cell exhaustion in the tumor microenvironment", J Immunother Cancer, 6, pp.144~ (2018)
- Chen X, "Hydrodynamic transfection for generation of novel mouse models for liver cancer research", Am J Pathol, 184, pp.912~923 (2014)
- Rumgay H, "Global burden of primary liver cancer in 2020 and predictions to 2040", J Hepatol, 77, pp.1598~1606 (2022)
- Fang Y, "A co-expression network reveals the potential regulatory mechanism of lncRNAs in relapsed hepatocellular carcinoma", Front Oncol, 11, pp.745166~ (2021)
- Karnoub AE, "Ras oncogenes : split personalities", Nat Rev Mol Cell Biol, 9, pp.517~531 (2008)
- Pylayeva-Gupta Y, "RAS oncogenes : weaving a tumorigenic web", Nat Rev Cancer, 11, pp.761~774 (2011)
- Mor A, "Compartmentalized Ras", MAPK signaling, 2006, pp.24, 771~800
- Cha PH, "Small-molecule binding of the axin RGS domain promotes β-catenin and Ras degradation", Nat Chem Biol, 12, pp.593~600 (2016)
- Moon BS, "Role of oncogenic K-Ras in cancer stem cell activation by aberrant Wnt", β-catenin signaling, 2014, pp.106, djt373~
- Calvisi DF, "Ubiquitous activation of Ras and Jak", Stat pathways in human HCC, 2006, pp.130, 1117~1128
- Chen L, "Expression and prognostic role of pan-Ras, Raf-1, pMEK1 and pERK1", 2 in patients with hepatocellular carcinoma, 2011, pp.37, 513~520
- Jura N, "Differential modification of Ras proteins by ubiquitination", Mol Cell, 21, pp.679~687 (2006)
- Sasaki AT, "Ubiquitination of K-Ras enhances activation and facilitates binding to select downstream effectors", Sci Signal, 4, pp.ra13~ (2011)
- Nacak TG, "The BTB-kelch protein LZTR-1 is a novel Golgi protein that is degraded upon induction of apoptosis", J Biol Chem, 281, pp.5065~5071 (2006)
- Piotrowski A, "Germline loss-of-function mutations in LZTR1predispose to an inherited disorder of multiple schwannomas", Nat Genet, 46, pp.182~187 (2014)