Low Levels of TRIM28-Interacting KRAB-ZNF Genes Associate with Cancer Stemness and Predict Poor Prognosis of Kidney Renal Clear Cell Carcinoma Patients

SIMPLE SUMMARY: This 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. ABSTRACT: 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.