TRIM28 in cancer and cancer therapy

Abstract

TRIM28 (tripartite motif protein 28) was initially believed to be a transcription inhibitor that plays an important role in DNA damage repair (DDR) and in maintaining cancer cellular stemness. As research has continued to deepen, several studies have found that TRIM28 not only has ubiquitin E3 ligase activity to promote degradation of substrates, but also can promote SUMOylation of substrates. Although TRIM28 is highly expressed in various cancer tissues and has oncogenic effects, there are still a few studies indicating that TRIM28 has certain anticancer effects. Additionally, TRIM28 is subject to complex upstream regulation. In this review, we have elaborated on the structure and regulation of TRIM28. At the same time, highlighting the functional role of TRIM28 in tumor development and emphasizing its impact on cancer treatment provides a new direction for future clinical antitumor treatment.

Keywords: SUMOylation; TRIM28; cancer therapy; transcription inhibitor; tumorigenesis; ubiquitination.

FIGURE 1

The structure and regulation of TRIM28. (A) The structure of TRIM28: TRIM28 consists of an N-terminal RING domain, two B-boxes (B1 and B2), a leucine zipper coiled-coil region (CC), an intermediate PxVxL pentapeptide domain, and a C-terminal plant homeodomain (PHD) and bromodomain. The RBCC domain, composed of the RING domain, B1 and B2 boxes, and CC domain, not only binds to the MAGE protein and functions as a ubiquitinated E3 ligase but also binds to the KRAB domain of the KRAB-ZNP protein. The PHD domain recruits NuRD and SETDB1 and the central PxVxL pentapeptide region binds to HP1. The transcriptional inhibitory activity of TRIM28 is closely related to its binding to SETDB1, NuRD, and HP1 proteins, but it is also influenced by SUMOylation modification of TRIM28 itself. The PHD domain has intrinsic E3 SUMO ligase activity. (B) The regulation of TRIM28.

FIGURE 2

The expression and mutation of the TRIM28 in human cancer (A) The expression of the TRIM28 in human cancer: The TRIM28 gene expression dataset from The Cancer Genome Atlas (TCGA) database was extracted to explore its differential expression between tumors and adjacent normal tissues (data from the TIMER2.0 database http://timer.cistrome. org). Boxplots represent the distribution of gene expression levels and the statistical significance of differential expression was assessed using the Wilcoxon test. An asterisk indicates a p-value less than 0.05, two asterisks indicate a p-value less than 0.01, and three asterisks indicate a p-value less than 0.001. As illustrated in the figure, TRIM28 was significantly overexpressed in BLCA, BRCA, CHOL, CRC, ESCA, HNSC, KIRC, LIHC, LUAD, LUSC, PRAD, STAD, THCA, and UCEC. THCA, thyroid carcinoma; LUSC: Lung squamous cell carcinoma; BLCA: Bladder urothelial carcinoma; LIHC: Liver hepatocellular carcinoma; PRAD: Prostate adenocarcinoma; KIRC: Kidney renal clear cell carcinoma; UCEC: Uterine corpus endometrial carcinoma; LUAD: Lung adenocarcinoma; STAD: Stomach adenocarcinoma; BRCA: Breast invasive carcinoma; CESC: Cervical squamous cell carcinoma and endocervical adenocarcinoma; CHOL: Cholangiocarcinoma; ESCA: Esophageal carcinoma; HNSC: Head and Neck squamous cell carcinoma; PAAD: Pancreatic adenocarcinoma; PCPG: Pheochromocytoma and Paraganglioma; THYM: Thymoma; CRC: Colorectal Cancer. (B) The point mutation of TRIM28 in cancer: Point mutation data of TRIM28 protein displayed on the cBioPortal platform (https://www.cbioportal.org/) in all cancers.

FIGURE 3

The role of TRIM28 in cancer TRIM28 protein, a ubiquitin E3 ligase, SUMO E3 ligase, or skeletal protein, plays an important role in the occurrence and development of tumors (including breast cancer, lung cancer, stomach cancer, liver cancer, colorectal cancer, prostate cancer, renal clear cell carcinoma, osteosarcoma melanoma, and neuroblastoma).