The tripartite motif-containing 24 is a multifunctional player in human cancer

Abstract

Tripartite motif-containing 24 (TRIM24), also known as transcriptional intermediary factor 1α (TIF1α), is the founding member of TIF1 family. Recent evidence indicates that aberrant expression of TRIM24, functions as an oncogene, is associated with poor prognosis across various cancer types. TRIM24 exhibits a multifaceted structure comprising an N-terminal TRIM region with a RING domain, B-box type 1 and type 2 domains, and a coiled-coil region, as well as a C-terminal plant-homeodomain (PHD)-bromodomain. The bromodomain serves as a 'reader' of epigenetic histone marks, regulating chromatin structure and gene expression by linking associated proteins to acetylated nucleosomal targets, thereby controlling transcription of genes. Notably, bromodomains have emerged as compelling targets for cancer therapeutic development. In addition, TRIM24 plays specialized roles as a signal transduction molecule, orchestrating various cellular signaling cascades in cancer cells. Herein, we review the recent advancements in understanding the functions of TRIM24, and demonstrate the research progress in utilizing TRIM24 as a target for cancer therapy.

Keywords: Cancer treatment; Cell proliferation; Epithelial–mesenchymal transition; TRIM24; Transcription regulation.

Fig. 1

Domain architecture of human TRIM24 (also called TIF1α) and other TIF1 family members, including TIF1β/TRIM28, TIF1γ/TRIM33, TIF1δ/TRIM66. RING: RING domain; B1 and B2: B-box domains; CC: coiled-coil domain; TSS: TIF1 signature sequence; HPBD: heterochromatin protein family binding domain; PHD: plant homeodomain finger; BROMO: bromodomain

Fig. 2

The schematic diagram illustrating how TRIM24 involves in transcription regulation by binding to specific histone sites via distinct domains. H3K23ac: acetylated Histone 3 lysine 23; H3K4me0: unmethylated Histone 3 lysine 4; H4K5ac: acetylated Histone 4 lysine 5; H4K8ac: acetylated Histone 4 lysine 8; KAT6A: lysine acetyltransferase 6A; DANCR: differentiation antagonizing non-protein coding RNA; TFs: Transcription factors

Fig. 3

The schematic diagram illustrating the TRIM24-mediated signaling pathway and its effectors in the regulation of cell proliferation. HSF1: heat shock transcription factor 1; STAT3: signal transducer and activator of transcription 3; AR: androgen receptor; ER: estrogen receptor; PIK3CA: phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; YAP1: Yes1 associated transcriptional regulator; p27: cyclin dependent kinase inhibitor 1B

Fig. 4

The regulatory mechanisms orchestrated by ATM, p53 and TRIM24 in response to DNA damage. DNA damage triggers the formation of MRN complexes, facilitating ATM activation. Activated ATM phosphorylates downstream substrates, including TRIM24, promoting its enrichment at DNA damage sites and amplifying the recruitment of MRN complex. Then, phosphorylated TRIM24, functioning as an E3 ligase, undergoes self-ubiquitination and degradation. p53 is another downstream substrate of ATM. Phosphorylated p53 induces TRIM24 transcription, and the newly synthesized TRIM24 promotes ubiquitination and degradation of phosphorylated p53, terminating the DNA damage response