Epigenetic silencing of Stk39 in B-cell lymphoma inhibits apoptosis from genotoxic stress.
B-cell lymphomas, the most frequent human immune system malignancies, often contain dysregulated TCL1 oncogene expression. TCL1 transgenic (TCL1-tg) mice develop a spectrum of B-cell malignancies, supporting an oncogenic role for TCL1 in B cells. Our prior global survey of DNA methylation patterns in TCL1-tg B-cell lymphomas identified many lymphoma-specific candidate hypermethylated genes, including Stk39. The Stk39 encoded protein, sterile 20-like-related proline-alanine-rich kinase (SPAK), regulates cell stress responses, and microarray studies identified reduced SPAK expression in metastatic prostate and treatment-resistant breast cancers, suggesting that its loss may have a role in cancer progression. Here we identified DNA hypermethylation and SPAK silencing in TCL1-tg B-cell lymphomas and SPAK silencing without DNA methylation in multiple subtypes of human B-cell lymphomas. SPAK knockdown by shRNA protected B cells from caspase-dependent apoptosis induced by DNA double-strand breaks but not apoptosis in response to osmotic or oxidative cell stressors. Caspase 3 activation by cleavage was impaired with SPAK repression in DNA damaged B cells. Interestingly, c-Jun NH(2)-terminal kinase is potentially activated by SPAK and pharmacological inhibition of c-Jun NH(2)-terminal kinase in SPAK-expressing B cells recapitulated the cell-protective phenotype of SPAK knockdown. Taken together, these data indicate that SPAK loss in B-cell lymphomas promotes increased cell survival with DNA damage and provides a potential mechanism for increased resistance to genotoxic stress in cancer.
Balatoni
Cynthia E
CE
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Dawson
David W
DW
Suh
Jane
J
Sherman
Mara H
MH
Sanders
Grant
G
Hong
Jason S
JS
Frank
Matthew J
MJ
Malone
Cindy S
CS
Said
Jonathan W
JW
Teitell
Michael A
MA
D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage; D019175:DNA Methylation; D004789:Enzyme Activation; D020868:Gene Silencing; D006801:Humans; D016393:Lymphoma, B-Cell / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism
D011518:Proto-Oncogene Proteins; C490393:Tcl1 protein, mouse; C486407:Stk39 protein, mouse; D017346:Protein Serine-Threonine Kinases; C486409:STK39 protein, human; D053148:Caspase 3