Abstract
Simple SummaryThis is the first report investigating the involvement of TRIM28-interacting KRAB-ZNFs in kidney cancer progression. We demonstrate a significant negative association between KRAB-ZNFs and cancer stemness followed by an attenuated immune-suppressive response and reveal the prognostic role for several KRAB-ZNFs. Our findings may help better understand the molecular basis of kidney cancer and ultimately pave the way to more appropriate prognostic tools and novel therapeutic strategies directly eradicating the dedifferentiated compartment of the tumor.Krüppel-associated box zinc finger (KRAB-ZNF) proteins are known to regulate diverse biological processes, such as embryonic development, tissue-specific gene expression, and cancer progression. However, their involvement in the regulation of cancer stemness-like phenotype acquisition and maintenance is scarcely explored across solid tumor types, and to date, there are no data for kidney renal clear cell cancer (KIRC). We have harnessed The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) database transcriptomic data and used several bioinformatic tools (i.e., GEPIA2, GSCALite, TISIDB, GSEA, CIBERSORT) to verify the relation between the expression and genomic alterations in KRAB-ZNFs and kidney cancer, focusing primarily on tumor dedifferentiation status and antitumor immune response. Our results demonstrate a significant negative correlation between KRAB-ZNFs and kidney cancer dedifferentiation status followed by an attenuated immune-suppressive response. The transcriptomic profiles of high KRAB-ZNF-expressing kidney tumors are significantly enriched with stem cell markers and show a depletion of several inflammatory pathways known for favoring cancer stemness. Moreover, we show for the first time the prognostic role for several KRAB-ZNFs in kidney cancer. Our results provide new insight into the role of selected KRAB-ZNF proteins in kidney cancer development. We believe that our findings may help better understand the molecular basis of KIRC.
Highlights
The largest class of DNA-binding transcription factors in mammalian cells, with more than 400 genes encoding for at least 700 members, is known as the Krüppel-associated box zinc finger (KRAB-ZNF) family [1]
We believe that our findings may help better understand the molecular basis of kidney renal clear cell cancer (KIRC) and pave the way to more appropriate prognostic tools for KIRC and facilitate the development of new therapeutic strategies directly targeting the dedifferentiated compartment of the tumor
Using the GSCALite database [16], we analyzed the expression of preselected KRABZNFs in The Cancer Genome Atlas (TCGA) KIRC tumor vs. normal adjacent tissue
Summary
The largest class of DNA-binding transcription factors in mammalian cells, with more than 400 genes encoding for at least 700 members, is known as the Krüppel-associated box zinc finger (KRAB-ZNF) family [1]. KRAB-ZNF proteins contain tandem copies of the C2H2 zinc finger DNA binding motif (ZNFs) accompanied with conserved Krüppelassociated box (KRAB) domain, which mediates the recruitment of a specific and universal corepressor—KRAB-associated protein 1 (KAP1), known as tripartite-motif containing 28 (TRIM28) or transcriptional intermediary factor 1β (TIF1β) [2]. TRIM28 is indispensable for transcriptional repression and gene silencing, acting as a scaffold protein for various heterochromatin-inducing factors, including histone deacetylases (nucleosome remodeling deacetylase (NuRD), histone methyltransferases (SET domain bifurcated 1 (SETDB1)), and heterochromatin proteins (heterochromatin protein 1 (HP1)). These proteins modify chromatin structure, leading to a compacted, silent state (epigenetic repression) [4]. To date, the direct interaction with TRIM28 has been confirmed experimentally only for several KRAB-ZNFs
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