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SUMOylation regulates nucleo-cytoplasmic shuttling of LKB1 in liver cancer

ABSTRACT: Even though liver kinase B1 (LKB1) is commonly described as a tumor suppressor, we and others have shown that LKB1 is augmented in liver cancer. In agreement, LKB1 modulation in human hepatoma cells and mouse livers induces changes in cell proliferation and the appearance of liver neoplastic lesions in association with disruptions of energetic metabolism. After LKB1 overexpression, a surprising uncoupling between LKB1 and its downstream kinase AMP-activated protein kinase is observed as well as activation of the oncogenic Ras pathway, driven by the direct or indirect binding of LKB1 to the promoter region of the Ras activator, RASGRP3. Under these circumstances, LKB1 SUMOylation at Lys178 by SUMO-2, the main SUMO paralogue present in liver, promotes LKB1 nuclear localization, fueling hepatoma cell proliferation. Overall, SUMO-2 mediated modification of LKB1 at Lys178 is suggested as a bona fide oncogenic driver in liver cancer by regulating the nucleo-cytoplasmic shuttling of LKB1.

ORGANISM(S): Mus musculus

PROVIDER: GSE99584 | GEO | 2018/09/11

REPOSITORIES: GEO

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Expression data from GNMT knockout mice in Hepatocytes and OKER cell lines

Project description:Hepatocellular carcinoma (HCC) is the first cause of death in cirrhotic patients. Liver cirrhosis at a high risk of HCC has abnormal S-Adenosylmethionine (SAMe) levels. Catabolism of SAMe is mainly mediated by Glycine N-methyltransferase (GNMT), Lack in GNMT expression leads to epigenetic regulation of critical carcinogenesis pathways and mounting evidence assigns an essential role of GNMT in HCC. Methods: Here we have studied the role of LKB1-AMPK and RAS in the proliferation and transformation of GNMT-deficient HCC. Results. GNMT-deficient HCC was characterized by LKB1-AMPK misconnection, leading to resistance of apoptosis response mediated by a positive regulation of cAMP-PKA-CaMKKM-NM-2 cascade. Additionally, Ras-mediated hyperactivation of LKB1 contributes to the proliferation of GNMT-deficient HCC in an ERK/p90RSK-dependent manner. The observed LKB1-induced Ras activation, was due to the regulation of RASGRP3 expression. Notably, the human HCC tumors with poorer prognosis showed the lowest levels of GNMT, p-AMPKM-NM-1(Thr172) and the highest activation of Ras/LKB1/RASGRP3 axis. The present data suggest a correlation between LKB1 and RAS activity in a context of HCC with low GNMT expression, indicating that activation of the RAS/LKB1/RASGRP3 cascade might possess an important prognostic role in human liver cancer. Furthermore, these findings open the possibility to design new therapeutic strategies for the treatment of liver cancer. HCC induced wild-type or Gnmt knockout mice at 3 weeks old were used for RNA extraction and hybridization on Illumina microarrays. The study comprises three groups of samples: OKER cell line(n=3), GNMT-KO mouse hepatocytes (n=3) ,GNMT-WT mouse hepatocytes(n=3)

2012-06-30 | E-GEOD-34838 | biostudies-arrayexpress

Expression data from GNMT knockout mice in Hepatocytes and OKER cell lines

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2012-07-01 | GSE34838 | GEO

LKB1/STK11 Inactivation Leads to Expansion of Pro-Metastatic Tumor Sub-Population in Melanoma

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2012-06-24 | E-GEOD-34866 | biostudies-arrayexpress

LKB1/STK11 Inactivation Leads to Expansion of Pro-Metastatic Tumor Sub-Population in Melanoma

2012-06-25 | GSE34866 | GEO

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2014-10-01 | E-GEOD-33613 | biostudies-arrayexpress

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Expression data from human primary fibroblasts (IMR90) stably expressing H-RasV12 and shRNA against ERK2 or a non-targeting shRNA

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