miRNA-130a targets ATG2B and DICER1 to inhibit autophagy and trigger killing of chronic lymphocytic leukemia cells

Valentina Kovaleva, Rodrigo Mora, Yoon Jung Park, Christoph Plass, Abhilash I. Chiramel, Ralf Bartenschlager, Hartmut Doḧner, Stephan Stilgenbauer, Armin Pscherer, Peter Lichter, Martina Seiffert

Research output: Contribution to journalArticlepeer-review

165 Scopus citations

Abstract

Toxicity and relapses from the immunochemotherapy used to treat chronic lymphocytic leukemia (CLL) prompt continued interest in gentle but effective targeted treatment options for the mainly elderly population suffering from this disease. Here, we report the definition of critical CLL cell survival pathways that can be targeted by ectopic reexpression of the miRNA genes miR-130a and miR-143 which are widely downregulated in CLL. Notably, miR-130a inhibited autophagy by reducing autophagosome formation, an effect mediated by downregulation of the genes ATG2B and DICER1, the latter of which is a major component of the miRNA silencing machinery. In support of the concept of a fundamental connection between miRNA disregulation and altered autophagic flux in this cancer, we showed that RNA interference-mediated knockdown of DICER1 expression was sufficient to reduce autophagy in primary or established cultures of CLL cells. Together, our findings show that miR-130a modulates cell survival programs by regulating autophagic flux, and they define roles for miR-130a and Dicer1 in a regulatory feedback loop that mediates CLL cell survival.

Original languageEnglish
Pages (from-to)1763-1772
Number of pages10
JournalCancer Research
Volume72
Issue number7
DOIs
StatePublished - 1 Apr 2012

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