Amplification at 11q23 targets protein kinase SIK2 in diffuse large B-cell lymphoma.
In diffuse large B-cell lymphoma (DLBCL), several recurrent chromosomal aberrations have been described where the presumed target genes remain unknown, including gain/amplification at 11q23-24. Here, we characterized amplification at 11q23 in the DLBCL cell line KARPAS-422. Quantitative genomic PCR and FISH analysis were used to define the region altered, thus showing an amplification peak at 111.1 Mb, the region hosting SIK2/SNF1LK2. Expression profiling, quantitative RT-PCR, Western blot, and immunocytology identified overexpression of SIK2, highlighting this gene as a likely key target of 11q23 amplification. SIK2 encodes a protein kinase that has been shown to inhibit transcription factor CREB via phosphorylation of its cofactor TORC2/CRTC2. Accordingly, siRNA-mediated downregulation of SIK2 expression resulted in upregulation of the CREB target gene BIM. Functional analysis by treatments with cAMP, the glucocorticoid dexamethasone, and 2-deoxy-d-glucose revealed a regulatory role for SIK2 in survival and glucose metabolism, respectively. However, overexpression of SIK2 was not detectable in primary DLBCL samples. Nevertheless, identification of SIK2 as an amplification target highlights this kinase along with its regulatory network as potential therapeutic targets in DLBCL.
Nagel
Stefan
S
Department of Human and Animal Cell Lines, DSMZ, German Collection of Microorganisms and Cell Cultures, Inhoffenstr. 7B, 38124 Braunschweig, Germany. sna@dsmz.de
Leich
Ellen
E
Quentmeier
Hilmar
H
Meyer
Corinna
C
Kaufmann
Maren
M
Zaborski
Margarete
M
Rosenwald
Andreas
A
Drexler
Hans G
HG
Macleod
Roderick A F
RA
D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics; D005784:Gene Amplification; D020869:Gene Expression Profiling; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D016403:Lymphoma, Large B-Cell, Diffuse / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D017346:Protein Serine-Threonine Kinases; C509080:SIK1 protein, human