LZAP, a putative tumor suppressor, selectively inhibits NF-kappaB.
LZAP has been reported to inhibit cellular proliferation and clonogenic growth. Here, we report that decreased LZAP expression promoted cellular transformation, xenograft tumor growth, and xenograft tumor vascularity. Loss of LZAP also increased cellular invasion, and MMP-9 expression dependent on NF-kappaB. LZAP directly bound to RelA, impaired serine 536 phosphorylation of RelA, increased HDAC association with RelA, inhibited basal and stimulated NF-kappaB transcriptional activity, and was found at the promoter of selective NF-kappaB-responsive genes. LZAP protein levels were markedly decreased in 32% of primary HNSCCs (n = 28) and decreased LZAP levels in primary HNSCC correlated with increased expression of the NF-kappaB-regulated genes IL-8 and IkappaBalpha. In aggregate, these data support a role of LZAP in NF-kappaB regulation and tumor suppression.
Wang
Jialiang
J
Department of Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA.
An
Hanbing
H
Mayo
Marty W
MW
Baldwin
Albert S
AS
Yarbrough
Wendell G
WG
D000818:Animals; D017209:Apoptosis; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006258:Head and Neck Neoplasms / Q000378:metabolism / Q000473:pathology; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009361:Neoplasm Invasiveness; D009419:Nerve Tissue Proteins / Q000502:physiology*; D051996:Transcription Factor RelA / Q000378:metabolism; D014183:Transplantation, Heterologous; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000502:physiology*