MicroRNA-31 sensitizes human breast cells to apoptosis by direct targeting of protein kinase C epsilon (PKCepsilon).
MicroRNAs post-transcriptionally regulate gene expression and thereby contribute to the modulation of numerous complex and disease-relevant cellular phenotypes, including cell proliferation, cell motility, apoptosis, and stress response. In breast cancer cell systems, miR-31 has been shown to inhibit cell migration, invasion, and metastasis. Here, we link enhanced expression of miR-31 to the inhibition of the oncogenic NF-κB pathway, thus supporting the tumor-suppressive function of this microRNA. We identified protein kinase C epsilon (PKCε encoded by the PRKCE gene) as a novel direct target of miR-31 and show that down-regulation of PKCε results in impaired NF-κB signaling, enhanced apoptosis, and increased sensitivity of MCF10A breast epithelial and MDA-MB-231 triple-negative breast cancer cells toward ionizing radiation as well as treatment with chemotherapeutics. Mechanistically, we attribute this sensitization to anti-cancer treatments to the PRKCE-mediated down-regulation of the anti-apoptotic factor BCL2. In clinical breast cancer samples, high BCL2 expression was associated with poor prognosis. Furthermore, we found an inverse correlation between miR-31 and BCL2 expression, highlighting the functional relevance of the indirect down-regulation of BCL2 via direct targeting of PRKCE by miR-31.
Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Cindy
C
Körner
Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Ioanna
I
Keklikoglou
Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Christian
C
Bender
Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Angelika
A
Wörner
Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Ewald
E
Münstermann
Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany. Electronic address: s.wiemann@dkfz-heidelberg.de.
Stefan
S
Wiemann
D020413:3' Untranslated Regions; D017209:Apoptosis; D001483:Base Sequence; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D002470:Cell Survival; D019008:Drug Resistance, Neoplasm; D005260:Female; D017930:Genes, Reporter; D006801:Humans; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D061986:MCF-7 Cells; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism; D051744:Protein Kinase C-epsilon / Q000235:genetics* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D011836:Radiation Tolerance; D019311:Staurosporine / Q000494:pharmacology; D020742:rhoA GTP-Binding Protein / Q000378:metabolism; D000097782:NF-kappaB-Inducing Kinase
D020413:3' Untranslated Regions; D008156:Luciferases; D035683:MicroRNAs; D016328:NF-kappa B; D051744:Protein Kinase C-epsilon; D017346:Protein Serine-Threonine Kinases; D019253:Proto-Oncogene Proteins c-bcl-2; D019311:Staurosporine; D020742:rhoA GTP-Binding Protein; D000097782:NF-kappaB-Inducing Kinase; C534612:MIRN31 microRNA, human; C066737:RHOA protein, human; C497255:PRKCE protein, human