TRIM16 acts as a tumour suppressor by inhibitory effects on cytoplasmic vimentin and nuclear E2F1 in neuroblastoma cells

Abstract

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 β2 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.

TRIM16 inhibits neuroblastoma cell proliferation through cell cycle regulation and dynamic nuclear localization

“…How the cell cycle machinery coordinates cell cycle arrest with differentiation activation is not fully understood in neuroblastoma. In vitro, TRIM16 overexpression induces or enhances keratinocyte and neuroblastoma differentiation, respectively 6 , 20 . We have also shown that in human neuroblastoma tissues, TRIM16 protein is only expressed in the differentiated ganglion cell component of human tumors.…”

“…Enforced overexpression of TRIM16 enhances neuronal differentiation in neuroblastoma cells, 6 suggesting that TRIM16 expression changes during neuroblast differentiation. To address this hypothesis, tissues from the histologically well-characterized TH-MYCN neuroblastoma mouse model were examined for TRIM16 protein expression 21 .…”

Roles and Potential Clinical Applications of Intermediate Filament Proteins in Brain Tumors

“…69 Vimentin was also shown to bind to the tripartite motif protein 16 (TRIM 16) in neuroblastoma cells, and the interaction between these 2 proteins was instrumental in regulating cell motility. 70 During development, lamin A/C is important in establishing and maintaining cellular differentiation. 4,11 It may play a similar role in neuroblastoma cells as suggested by the finding that silencing lamin A/C in these cells inhibited retinoic acid-induced differentiation, stimulated proliferative activity, increased tumor formation in a mouse model, and enhanced resistance to several therapeutic agents, including etoposide, doxorubicin, and paclitaxel.…”

Antiviral TRIMs: friend or foe in autoimmune and autoinflammatory disease?

“…Whether the correlation between TRIM16 expression and enhanced invasiveness is as a result of altered TRIM16 regulation of IL-1β secretion remains to be elucidated. Recently TRIM16 has been shown to bind and degrade vimentin in tumours [102]. Vimentin is a member of the intermediate filament family of proteins and presence of autoantibodies that recognise a citrulinated from of vimentin are strongly associated with RA and are used as both a diagnostic and prognostic marker.…”