BRMS1 contributes to the negative regulation of uPA gene expression through recruitment of HDAC1 to the NF-κB binding site of the uPA promoter

Abstract

The BRMS1 metastasis suppressor was recently shown to negatively regulate NF-κB signaling and down regulate NF-κB-dependent uPA expression. Here we confirm that BRMS1 expression correlates with reduced NF-κB DNA binding activity in independently derived human melanoma C8161.9 cells stably expressing BRMS1. We show that knockdown of BRMS1 expression in these cells using small interfering RNA (siRNA) leads to the reactivation of NF-κB DNA binding activity and re-expression of uPA. Further, we confirm that BRMS1 expression does not alter IKKß kinase activity suggesting that BRMS1-dependent uPA regulation does not occur through inhibition of the classical upstream activators of NF-κB. BRMS1 has been implicated as a corepressor of HDAC1 and consistent with this, we show that BRMS1 promotes HDAC1 recruitment to the NF-κB binding site of the uPA promoter and is associated with reduced H3 acetylation. We also confirm that BRMS1 expression stimulates disassociation of p65 from the NF-κB binding site of the uPA promoter consistent with its reduced DNA binding activity. These data suggest that BRMS1 recruits HDAC1 to the NF-κB binding site of the uPA promoter, modulates histone acetylation of p65 on the uPA promoter, leading to reduced NF-κB binding activity on its consensus sequence, and reduced transactivation of uPA expression.

Cell Cycle Regulator ING4 Is a Suppressor of Melanoma Angiogenesis That Is Regulated by the Metastasis Suppressor BRMS1

“…Collectively, these data indicated that ING4 regulated HUVEC growth through decreasing IL-6 level. We next investigated whether ING4 collaborated with BRMS1 in this angiogenesis modulation, as both ING4 and BRMS1 inhibited melanoma angiogenesis through NF-kB/IL-6 pathway, and both were reported to inhibit NF-kB activity (21,28,30,31). The immunoprecipitation data showed that ING4 and BRMS1 cannot be precipitated together, ruling out the possibility that they functioned in the same complex (Supplementary Fig.…”

PKD2 and PKD3 Promote Prostate Cancer Cell Invasion via uPA by Shifting Balance Between NF-κB and HDAC1

“…Quantitative PCR of coimmunoprecipitated genomic DNA fragments was performed with the following promoter-specific primers: uPA-NF-kB sense, 59-GAGGGGGCGGAAGGGG-AGAA-39 and uPA-NF-kB antisense, 59-TGTGGTCAGTTTTGTTTGGATTTG-39 (Cicek et al, 2009); and nonpromoter sequence primers of the uPAencoding gene: uPA-EXO11 sense, 59-TTGTATCTTTGGCGTCACAGG-39 and uPA-EXO11 antisense, 59-CATTCTCTTCCTTGGTGTGAC-39 (Ibañez -Tallon et al, 2002).…”

Ectopic expression of RhoBTB2 inhibits migration and invasion of human breast cancer cells

“…BRMS1 expression results in a decrease of IκBα phosphorylation and reduce the nuclear translocation of p65 and p50. [24][25][26] However, it remains currently unknown whether RhoBTB2 contributes to the regulation of BRMS1 in human breast cancer cells.…”

“…Since BRMS1 has been shown to suppress metastasis of metastatic human breast cancer, [19][20][21][22][23][24][25][26] we proposed the hypothesis that BRMS1 was involved in RhoBTB2-induced suppression of…”