Murine double minute 2 regulates Hu antigen R stability in human liver and colon cancer through NEDDylation

Nieves Embade, David Fernández-Ramos, Marta Varela-Rey, Naiara Beraza, Marcella Sini, Virginia Gutiérrez de Juan, Ashwin Woodhoo, Nuria Martínez-López, Begoña Rodríguez-Iruretagoyena, Francisco Javier Bustamante, Ana Belén de la Hoz, Arkaitz Carracedo, Dimitris P. Xirodimas, Manuel S. Rodríguez, Shelly C. Lu, José M. Mato, María L. Martínez-Chantar

Research output: Contribution to journalArticle

58 Citations (Scopus)

Abstract

Hu antigen R (HuR) is a central RNA-binding protein regulating cell dedifferentiation, proliferation, and survival, which are well-established hallmarks of cancer. HuR is frequently overexpressed in tumors correlating with tumor malignancy, which is in line with a role for HuR in tumorigenesis. However, the precise mechanism leading to changes in HuR expression remains unclear. In the liver, HuR plays a crucial role in hepatocyte proliferation, differentiation, and transformation. Here, we unraveled a novel mean of regulation of HuR expression in hepatocellular carcinoma (HCC) and colon cancer. HuR levels correlate with the abundance of the oncogene, murine double minute 2 (Mdm2), in human HCC and colon cancer metastases. HuR is stabilized by Mdm2-mediated NEDDylation in at least three lysine residues, ensuring its nuclear localization and protection from degradation. Conclusion: This novel Mdm2/NEDD8/HuR regulatory framework is essential for the malignant transformation of tumor cells, which, in turn, unveils a novel signaling paradigm that is pharmacologically amenable for cancer therapy.

Original languageEnglish (US)
Pages (from-to)1237-1248
Number of pages12
JournalHepatology
Volume55
Issue number4
DOIs
StatePublished - Apr 2012
Externally publishedYes

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ELAV Proteins
Liver Neoplasms
Colonic Neoplasms
Neoplasms
Hepatocellular Carcinoma
Cell Dedifferentiation
RNA-Binding Proteins
Oncogenes
Lysine
Hepatocytes
Cell Survival
Carcinogenesis
Cell Proliferation

ASJC Scopus subject areas

  • Hepatology

Cite this

Embade, N., Fernández-Ramos, D., Varela-Rey, M., Beraza, N., Sini, M., de Juan, V. G., ... Martínez-Chantar, M. L. (2012). Murine double minute 2 regulates Hu antigen R stability in human liver and colon cancer through NEDDylation. Hepatology, 55(4), 1237-1248. https://doi.org/10.1002/hep.24795

Murine double minute 2 regulates Hu antigen R stability in human liver and colon cancer through NEDDylation. / Embade, Nieves; Fernández-Ramos, David; Varela-Rey, Marta; Beraza, Naiara; Sini, Marcella; de Juan, Virginia Gutiérrez; Woodhoo, Ashwin; Martínez-López, Nuria; Rodríguez-Iruretagoyena, Begoña; Bustamante, Francisco Javier; de la Hoz, Ana Belén; Carracedo, Arkaitz; Xirodimas, Dimitris P.; Rodríguez, Manuel S.; Lu, Shelly C.; Mato, José M.; Martínez-Chantar, María L.

In: Hepatology, Vol. 55, No. 4, 04.2012, p. 1237-1248.

Research output: Contribution to journalArticle

Embade, N, Fernández-Ramos, D, Varela-Rey, M, Beraza, N, Sini, M, de Juan, VG, Woodhoo, A, Martínez-López, N, Rodríguez-Iruretagoyena, B, Bustamante, FJ, de la Hoz, AB, Carracedo, A, Xirodimas, DP, Rodríguez, MS, Lu, SC, Mato, JM & Martínez-Chantar, ML 2012, 'Murine double minute 2 regulates Hu antigen R stability in human liver and colon cancer through NEDDylation', Hepatology, vol. 55, no. 4, pp. 1237-1248. https://doi.org/10.1002/hep.24795
Embade N, Fernández-Ramos D, Varela-Rey M, Beraza N, Sini M, de Juan VG et al. Murine double minute 2 regulates Hu antigen R stability in human liver and colon cancer through NEDDylation. Hepatology. 2012 Apr;55(4):1237-1248. https://doi.org/10.1002/hep.24795
Embade, Nieves ; Fernández-Ramos, David ; Varela-Rey, Marta ; Beraza, Naiara ; Sini, Marcella ; de Juan, Virginia Gutiérrez ; Woodhoo, Ashwin ; Martínez-López, Nuria ; Rodríguez-Iruretagoyena, Begoña ; Bustamante, Francisco Javier ; de la Hoz, Ana Belén ; Carracedo, Arkaitz ; Xirodimas, Dimitris P. ; Rodríguez, Manuel S. ; Lu, Shelly C. ; Mato, José M. ; Martínez-Chantar, María L. / Murine double minute 2 regulates Hu antigen R stability in human liver and colon cancer through NEDDylation. In: Hepatology. 2012 ; Vol. 55, No. 4. pp. 1237-1248.
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abstract = "Hu antigen R (HuR) is a central RNA-binding protein regulating cell dedifferentiation, proliferation, and survival, which are well-established hallmarks of cancer. HuR is frequently overexpressed in tumors correlating with tumor malignancy, which is in line with a role for HuR in tumorigenesis. However, the precise mechanism leading to changes in HuR expression remains unclear. In the liver, HuR plays a crucial role in hepatocyte proliferation, differentiation, and transformation. Here, we unraveled a novel mean of regulation of HuR expression in hepatocellular carcinoma (HCC) and colon cancer. HuR levels correlate with the abundance of the oncogene, murine double minute 2 (Mdm2), in human HCC and colon cancer metastases. HuR is stabilized by Mdm2-mediated NEDDylation in at least three lysine residues, ensuring its nuclear localization and protection from degradation. Conclusion: This novel Mdm2/NEDD8/HuR regulatory framework is essential for the malignant transformation of tumor cells, which, in turn, unveils a novel signaling paradigm that is pharmacologically amenable for cancer therapy.",
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AU - Beraza, Naiara

AU - Sini, Marcella

AU - de Juan, Virginia Gutiérrez

AU - Woodhoo, Ashwin

AU - Martínez-López, Nuria

AU - Rodríguez-Iruretagoyena, Begoña

AU - Bustamante, Francisco Javier

AU - de la Hoz, Ana Belén

AU - Carracedo, Arkaitz

AU - Xirodimas, Dimitris P.

AU - Rodríguez, Manuel S.

AU - Lu, Shelly C.

AU - Mato, José M.

AU - Martínez-Chantar, María L.

PY - 2012/4

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N2 - Hu antigen R (HuR) is a central RNA-binding protein regulating cell dedifferentiation, proliferation, and survival, which are well-established hallmarks of cancer. HuR is frequently overexpressed in tumors correlating with tumor malignancy, which is in line with a role for HuR in tumorigenesis. However, the precise mechanism leading to changes in HuR expression remains unclear. In the liver, HuR plays a crucial role in hepatocyte proliferation, differentiation, and transformation. Here, we unraveled a novel mean of regulation of HuR expression in hepatocellular carcinoma (HCC) and colon cancer. HuR levels correlate with the abundance of the oncogene, murine double minute 2 (Mdm2), in human HCC and colon cancer metastases. HuR is stabilized by Mdm2-mediated NEDDylation in at least three lysine residues, ensuring its nuclear localization and protection from degradation. Conclusion: This novel Mdm2/NEDD8/HuR regulatory framework is essential for the malignant transformation of tumor cells, which, in turn, unveils a novel signaling paradigm that is pharmacologically amenable for cancer therapy.

AB - Hu antigen R (HuR) is a central RNA-binding protein regulating cell dedifferentiation, proliferation, and survival, which are well-established hallmarks of cancer. HuR is frequently overexpressed in tumors correlating with tumor malignancy, which is in line with a role for HuR in tumorigenesis. However, the precise mechanism leading to changes in HuR expression remains unclear. In the liver, HuR plays a crucial role in hepatocyte proliferation, differentiation, and transformation. Here, we unraveled a novel mean of regulation of HuR expression in hepatocellular carcinoma (HCC) and colon cancer. HuR levels correlate with the abundance of the oncogene, murine double minute 2 (Mdm2), in human HCC and colon cancer metastases. HuR is stabilized by Mdm2-mediated NEDDylation in at least three lysine residues, ensuring its nuclear localization and protection from degradation. Conclusion: This novel Mdm2/NEDD8/HuR regulatory framework is essential for the malignant transformation of tumor cells, which, in turn, unveils a novel signaling paradigm that is pharmacologically amenable for cancer therapy.

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