The Association between TIF1 Family Members and Cancer Stemness in Solid Tumors

Abstract

Simple SummaryStem cell-associated molecular features of solid tumors, collectively known as cancer stemness, are of great importance in the development, progression, and reoccurrence of cancer. Transcriptional and epigenetic dysregulation is significantly associated with cancer stemness. Here, we investigated the association between the Transcriptional Intermediary Factor 1 (TIF1) family members and cancer stemness in solid tumors. We aimed to evaluate the potential value of TIF1 members in predicting a stem-like cancer phenotype. Our results indicate that only TIF1β (also known as Tripartite Motif protein 28, TRIM28) high expression is consequently associated with a “stemness high” phenotype, regardless of the tumor type, resulting in a worse prognosis for cancer patients. The oncogenic signature of TRIM28HIGH tumors significantly reflects the enrichment of “stemness high” cancers with targets for c-Myc (MYC Proto-Oncogene). TRIM28-associated gene expression profiles are also robustly enriched with stemness markers. Our results demonstrate that the association between high TRIM28 expression and an enriched cancer stem cell-like phenotype is a common phenomenon across solid tumors.Cancer progression entails a gradual loss of a differentiated phenotype in parallel with the acquisition of stem cell-like features. Cancer de-differentiation and the acquisition of stemness features are mediated by the transcriptional and epigenetic dysregulation of cancer cells. Here, using publicly available data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases and harnessing several bioinformatic tools, we characterized the association between Transcriptional Intermediary Factor 1 (TIF1) family members and cancer stemness in 27 distinct types of solid tumors. We aimed to define the prognostic value for TIF1 members in predicting a stem cell-like cancer phenotype and patient outcome. Our results demonstrate that high expression of only one member of the TIF1 family, namely TIF1β (also known as Tripartite Motif protein 28, TRIM28) is consequently associated with enriched cancer stemness across the tested solid tumor types, resulting in a worse prognosis for cancer patients. TRIM28 is highly expressed in higher grade tumors that exhibit stem cell-like traits. In contrast to other TIF1 members, only TIF1β/TRIM28-associated gene expression profiles were robustly enriched with stemness markers regardless of the tumor type. Our work demonstrates that TIF1 family members exhibit distinct expression patterns in stem cell-like tumors, despite their structural and functional similarity. Among other TIF1 members, only TRIM28 might serve as a marker of cancer stemness features.