TRIM16 acts as a tumour suppressor by inhibitory effects on cytoplasmic vimentin and nuclear E2F1 in neuroblastoma cells.
The family of tripartite-motif (TRIM) proteins are involved in diverse cellular processes, but are often characterized by critical protein-protein interactions necessary for their function. TRIM16 is induced in different cancer types, when the cancer cell is forced to proceed down a differentiation pathway. We have identified TRIM16 as a DNA-binding protein with histone acetylase activity, which is required for the retinoic acid receptor β(2) transcriptional response in retinoid-treated cancer cells. In this study, we show that overexpressed TRIM16 reduced neuroblastoma cell growth, enhanced retinoid-induced differentiation and reduced tumourigenicity in vivo. TRIM16 was only expressed in the differentiated ganglion cell component of primary human neuroblastoma tumour tissues. TRIM16 bound directly to cytoplasmic vimentin and nuclear E2F1 in neuroblastoma cells. TRIM16 reduced cell motility and this required downregulation of vimentin. Retinoid treatment and enforced overexpression caused TRIM16 to translocate to the nucleus, and bind to and downregulate nuclear E2F1, required for cell replication. This study, for the first time, demonstrates that TRIM16 acts as a tumour suppressor, affecting neuritic differentiation, cell migration and replication through interactions with cytoplasmic vimentin and nuclear E2F1 in neuroblastoma cells.
Marshall
G M
GM
Children's Cancer Institute Australia for Medical Research, Randwick, New South Wales, Australia.
Bell
J L
JL
Koach
J
J
Tan
O
O
Kim
P
P
Malyukova
A
A
Thomas
W
W
Sekyere
E O
EO
Liu
T
T
Cunningham
A M
AM
Tobias
V
V
Norris
M D
MD
Haber
M
M
Kavallaris
M
M
Cheung
B B
BB
D000818:Animals; D002454:Cell Differentiation; D002465:Cell Movement; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000502:physiology*; D050687:E2F1 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009447:Neuroblastoma / Q000473:pathology*; D014157:Transcription Factors / Q000502:physiology*; D000070584:Tripartite Motif Proteins; D025521:Tumor Suppressor Proteins / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases; D014746:Vimentin / Q000037:antagonists & inhibitors* / Q000502:physiology
D004268:DNA-Binding Proteins; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D014157:Transcription Factors; D000070584:Tripartite Motif Proteins; D025521:Tumor Suppressor Proteins; D014746:Vimentin; C117731:TRIM16 protein, human; D044767:Ubiquitin-Protein Ligases