Oncotarget

Research Papers:

Keap1/Nrf2 pathway in kidney cancer: frequent methylation of KEAP1 gene promoter in clear renal cell carcinoma

Federico Pio Fabrizio, Manuela Costantini, Massimiliano Copetti, Annamaria la Torre, Angelo Sparaneo, Andrea Fontana, Luana Poeta, Michele Gallucci, Steno Sentinelli, Paolo Graziano, Paola Parente, Vincenzo Pompeo, Laura De Salvo, Giuseppe Simone, Rocco Papalia, Francesco Picardo, Teresa Balsamo, Gerardo Paolo Flammia, Domenico Trombetta, Angela Pantalone, Klaas Kok, Ferronika Paranita, Lucia Anna Muscarella _ and Vito Michele Fazio

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Oncotarget. 2017; 8:11187-11198. https://doi.org/10.18632/oncotarget.14492

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Abstract

Federico Pio Fabrizio1,*, Manuela Costantini2,5,4,*, Massimiliano Copetti3, Annamaria la Torre1, Angelo Sparaneo1, Andrea Fontana3, Luana Poeta4, Michele Gallucci5, Steno Sentinelli6, Paolo Graziano7, Paola Parente7, Vincenzo Pompeo5, Laura De Salvo6, Giuseppe Simone5, Rocco Papalia5, Francesco Picardo2, Teresa Balsamo1, Gerardo Paolo Flammia8, Domenico Trombetta1, Angela Pantalone2, Klaas Kok9, Ferronika Paranita9, Lucia Anna Muscarella1,*, Vito Michele Fazio1,2,*

1Laboratory of Oncology, IRCCS “Casa Sollievo della Sofferenza” Hospital, San Giovanni Rotondo, Italy

2Genetic and Clinic Pathology Unit, University Campus Bio-Medico of Rome, Rome, Italy

3Unit of Biostatistics, IRCCS “Casa Sollievo della Sofferenza” Hospital, San Giovanni Rotondo, Italy

4Department of Bioscience, Biotechnology and Biopharmaceutics, University of Bari, Bari, Italy

5Department of Urology, Regina Elena National Cancer Institute, Rome, Italy

6Department of Pathology, Regina Elena National Cancer Institute, Rome, Italy

7Unit of Pathology, IRCCS “Casa Sollievo della Sofferenza” Hospital, San Giovanni Rotondo, Italy

8UOC of Urology, Campus Bio-Medico University Hospital, Rome, Italy

9Department of Genetics, University of Groningen, University Medical Center Groningen, The Netherlands

*These authors equally contributed to this work

Correspondence to:

Lucia Anna Muscarella, email: [email protected]

Keywords: ccRCC, KEAP1, methylation, epigenetic biomarker, outcome

Received: June 13, 2016     Accepted: December 27, 2016     Published: January 04, 2017

ABSTRACT

The Keap1/Nrf2 pathway is a master regulator of the cellular redox state through the induction of several antioxidant defence genes implicated in chemotherapeutic drugs resistance of tumor cells. An increasing body of evidence supports a key role for Keap1/Nrf2 pathway in kidney diseases and renal cell carcinoma (RCC), but data concerning the molecular basis and the clinical effect of its deregulation remain incomplete.

Here we present a molecular profiling of the KEAP1 and NFE2L2 genes in five different Renal Cell Carcinoma histotypes by analysing 89 tumor/normal paired tissues (clear cell Renal Carcinoma, ccRCCs; Oncocytomas; Papillary Renal Cell Carcinoma Type 1, PRCC1; Papillary Renal Cell Carcinoma Type 2, PRCC2; and Chromophobe Cell Carcinoma).

A tumor-specific DNA methylation of the KEAP1 gene promoter region was found as a specific feature of the ccRCC subtype (18/37, 48.6%) and a direct correlation with mRNA levels was confirmed by in vitro 5-azacytidine treatment. Analysis of an independent data set of 481 ccRCC and 265 PRCC tumors corroborates our results and multivariate analysis reveals a significant correlation among ccRCCs epigenetic KEAP1 silencing and staging, grading and overall survival.

Our molecular results show for the the first time the epigenetic silencing of KEAP1 promoter as the leading mechanism for modulation of KEAP1 expression in ccRCCs and corroborate the driver role of Keap1/Nrf2 axis deregulation with potential new function as independent epigenetic prognostic marker in renal cell carcinoma.


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