The complexity of TRIM28 contribution to cancer

Abstract

Since the first discovery in 1996, the engagement of TRIM28 in distinct aspects of cellular biology has been extensively studied resulting in identification of a complex nature of TRIM28 protein. In this review, we summarize core biological functions of TRIM28 that emerge from TRIM28 multi-domain structure and possessed enzymatic activities. Moreover, we will discuss whether the complexity of TRIM28 engagement in cancer biology makes TRIM28 a possible candidate for targeted anti-cancer therapy. Briefly, we will demonstrate the role of TRIM28 in regulation of target gene transcription, response to DNA damage, downregulation of p53 activity, stimulation of epithelial-to-mesenchymal transition, stemness sustainability, induction of autophagy and regulation of retrotransposition, to provide the answer whether TRIM28 functions as a stimulator or inhibitor of tumorigenesis. To date, number of studies demonstrate significant upregulation of TRIM28 expression in cancer tissues which correlates with worse overall patient survival, suggesting that TRIM28 supports cancer progression. Here, we present distinct aspects of TRIM28 involvement in regulation of cancer cell homeostasis which collectively imply pro-tumorigenic character of TRIM28. Thorough analyses are further needed to verify whether TRIM28 possess the potential to become a new anti-cancer target.

The role of TRIM family proteins in the regulation of cancer stem cell self-renewal

“…TRIM28 , also known as TIF1β or KAP1 (Krüppel‐Associated Box [KRAB]‐Associated Protein 1) protein, was first described as a universal cofactor for a huge family of KRAB Zinc Finger Protein transcription factors . TRIM28 is strictly associated with the maintenance of stem cell self‐renewal and contributes to the stemness machinery on several distinct levels.…”

“…In both cases, the TRIM motif plays an essential role in forming a supramolecular assembly. 8,15,41,68 The E3 ubiquitin ligase activity mediated by the RING domain is commonly used by specific TRIM proteins to exert the stem cell-associated function. Besides the abovementioned targets for ubiquitination and proteasomal degradation, the level of several other proteins is tightly regulated by TRIM members to maintain the pluripotent state (ie, components of the cell cycle regulatory circuit [p53] or proteins associated with cell metabolism [AMPK]).…”

“…Moreover, TRIM24 converges with Oct-3/4, Sox2, and NANOG on multiple enhancers and suppresses the expression of developmental genes to support the pluripotent state of stem cells 45. TRIM28, also known as TIF1β or KAP1 (Krüppel-Associated Box[KRAB]-Associated Protein 1) protein, was first described as a universal cofactor for a huge family of KRAB Zinc Finger Protein transcription factors 8. TRIM28 is strictly associated with the maintenance of stem cell self-renewal and contributes to the stemness machinery on several distinct levels.…”

TRIM28 and TRIM27 are required for expressions of PDGFRβ and contractile phenotypic genes by vascular smooth muscle cells

“…Tripartite motif‐containing (TRIM) proteins belong to the tripartite motif family and contain one coiled‐coil region and three zinc‐binding domains including one RING, one B‐box type 1, and one B‐box type 2 domains. Previous studies have shown that TRIM family proteins play important roles in transcriptional control, viral suppression, energy metabolism, development and cellular differentiation, immune response, proliferation, cancer and genome stability, etc Results from others and our group have shown that tripartite motif‐containing 28 (TRIM28) mediates the differentiation of murine embryonic stem cells into cardiomyocytes, angiogenesis, and endothelial inflammatory response . Tripartite motif‐containing 27 (TRIM27) is involved in cell proliferation and transcriptional repression .…”

Inhibition of HIV-1 gene transcription by KAP1 in myeloid lineage

“…CTIP2 and KAP1 are highly expressed in resting T cells and depleted upon activation (31,56). In addition, increased levels of CTIP2 are associated with persistence of HIV-1 latency in the brain (14) and increased level of KAP1 in the peripheral blood of gastric cancer patients is a biomarker predicting cancer stage progression (57)(58)(59)(60). By transposition to what has been observed in oncology and virology, these repressors and their associated enzymatic activities may constitute good targets in therapies aiming at curing the HIV-1 infected patients…”