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

Abstract

The long non-coding RNA (lncRNA) NKILA, 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 NKILA, 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, NKILA methylation was detected in 1/10 (10%) NHL cell lines, but not in normal peripheral blood buffy coats or tonsils. NKILA methylation correlated with the repression of NKILA in cell lines. Hypomethylation treatment with 5-Aza-2′-deoxycytidine resulted in promoter demethylation and the re-expression of NKILA. In 102 NHL primary samples, NKILA 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 NKILA 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 NKILA in SU-DHL-1 cells led to decreased cell death and increased cellular proliferation. Collectively, NKILA was a tumor suppressor lncRNA frequently hypermethylated in DLBCL. Promoter DNA methylation-mediated NKILA silencing resulted in increased cellular proliferation and decreased cell death via the repression of NF-κB signaling in NHL.

NKILA is a novel suppressor of local recurrence in women breast malignant phyllodes tumor patients via inhibition of the NF-κB pathway

“…Increased expression of NKILA has been shown to inhibit the proliferation, migration and metastasis of tumor cells, including breast cancer cells [ 10 ], non-Hodgkinś lymphoma cells [ 26 ], and colon adenocarcinoma cells [ 27 ]. Similarly, the present study demonstrated that increased expression of NKILA inhibited the migration, invasion and proliferation of primary recurrent BMPT cells, which suggested that NKILA suppresses the malignant behaviors of BMPT cells.…”

Crosstalk between Noncoding RNAs and the Epigenetics Machinery in Pediatric Tumors and Their Microenvironment

“…NKILA inhibits the phosphorylation of IκBα, which prevents its degradation and the subsequent nuclear translocation of both total and phosphorylated p65, a key component of the NF-κB complex. Repression of the NF-κB signaling pathway plays a critical role in regulating NKILAmediated tumor suppressive functions [109].…”

Mutual interaction of lncRNAs and epigenetics: focusing on cancer

“…has revealed that the tumor suppressor lncRNA NKILA is silenced duo2 to promoter hypermethylation in diffuse large B-cell lymphoma (DLBCL). NKILA is an NF-κB inhibitor so this downregulation leads to cancer progression [63]. In addition to the mentioned cases, other cancers have also been studied in this regard.…”