Epigenetic Silencing of Tumor Suppressor lncRNA : Implication on NF-κB Signaling in Non-Hodgkin's Lymphoma.

The long non-coding RNA (lncRNA) localized to 20q13.31, is a negative regulator of NF-κB signaling implicated in carcinogenesis. As a CpG island is embedded in the promoter region of , it is hypothesized as a tumor suppressor lncRNA silenced by promoter DNA methylation in non-Hodgkin's lymphoma (NHL). By pyrosequencing-verified methylation-specific PCR, methylation was detected in 1/10 (10%) NHL cell lines, but not in normal peripheral blood buffy coats or tonsils. methylation correlated with the repression of in cell lines. Hypomethylation treatment with 5-Aza-2'-deoxycytidine resulted in promoter demethylation and the re-expression of . In 102 NHL primary samples, was methylated in 29 (51.79%) diffuse large B-cell lymphoma (DLBCL) and 4 (20%) peripheral T-cell lymphoma cases, but unmethylated in all 26 mantle cell lymphoma cases. Mechanistically, the knockdown of resulted in promoting IkBα phosphorylation, associated with nucleus translocation of total p65 and phosphorylated p65 in SU-DHL-1 cells, hence constitutive NF-κB activation. Functionally, the knockdown of in SU-DHL-1 cells led to decreased cell death and increased cellular proliferation. Collectively, was a tumor suppressor lncRNA frequently hypermethylated in DLBCL. Promoter DNA methylation-mediated silencing resulted in increased cellular proliferation and decreased cell death via the repression of NF-κB signaling in NHL.