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 PantaloneKlaas Kok, Ferronika Paranita, L. A. Muscarella, Vito Michele Fazio

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)11187-11198
Number of pages12
JournalOncotarget
Volume8
Issue number7
DOIs
Publication statusPublished - Jan 1 2017

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Keywords

  • ccRCC
  • Epigenetic biomarker
  • KEAP1
  • Methylation
  • Outcome

ASJC Scopus subject areas

  • Oncology

Cite this

Fabrizio, F. P., Costantini, M., Copetti, M., la Torre, A., Sparaneo, A., Fontana, A., Poeta, L., Gallucci, M., Sentinelli, S., Graziano, P., Parente, P., Pompeo, V., Salvo, L. D., Simone, G., Papalia, R., Picardo, F., Balsamo, T., Flammia, G. P., Trombetta, D., ... Fazio, V. M. (2017). Keap1/Nrf2 pathway in kidney cancer: Frequent methylation of KEAP1 gene promoter in clear renal cell carcinoma. Oncotarget, 8(7), 11187-11198. https://doi.org/10.18632/oncotarget.14492