The expression signature of cancer‐associated KRAB‐ZNF factors identified in TCGA pan‐cancer transcriptomic data

Abstract

The KRAB ‐ ZNF (Krüppel‐associated box domain zinc finger) gene family is composed of a large number of highly homologous genes, gene isoforms, and pseudogenes. The proteins encoded by these genes, whose expression is often tissue‐specific, act as epigenetic suppressors contributing to the addition of repressive chromatin marks and DNA methylation. Due to its high complexity, the KRAB ‐ ZNF family has not been studied in sufficient detail, and the involvement of its members in carcinogenesis remains mostly unexplored. In this study, we aimed to provide a comprehensive description of cancer‐associated KRAB ‐ ZNF s using publicly available The Cancer Genome Atlas pan‐cancer datasets. We analyzed 6727 tumor and normal tissue samples from 16 cancer types. Here, we showed that a small but distinctive cluster of 16 KRAB ‐ ZNF s is commonly upregulated across multiple cancer cohorts in comparison to normal samples. We confirmed these observations in the independent panels of lung and breast cancer cell lines and tissues. This upregulation was also observed for most of the KRAB ‐ ZNF splicing variants, whose expression is simultaneously upregulated in tumors compared to normal tissues. Finally, by analyzing the clinicopathological data for breast and lung cancers, we demonstrated that the expression of cancer‐associated KRAB ‐ ZNF s correlates with patient survival, tumor histology, and molecular subtyping. Altogether, our study allowed the identification and characterization of KRAB ‐ ZNF factors that may have an essential function in cancer biology and thus potential to become novel oncologic biomarkers and treatment targets.

Endogenous retroviruses are a source of enhancers with oncogenic potential in acute myeloid leukaemia

“…4b , right). Interestingly, ZNF320 is also upregulated in multiple cancer types 45 . ZNF320 is a member of the Krüppel-associated box (KRAB) domain zinc finger family and predominantly binds LTR14A and LTR14B elements 46 , suggesting a potential role in ERV silencing.…”

Endogenous retroviruses are a source of enhancers with oncogenic potential in acute myeloid leukaemia

“…Notably, all three genes display higher expression in AML samples when compared to monocytes and macrophages ( Figure 4B, right). Interestingly, ZNF320 is also upregulated in multiple cancer types (Machnik et al, 2019), but its relevance to cancer etiology remains unclear. ZNF320 is a member of the Krüppel-associated box (KRAB) domain zinc finger family and predominantly binds LTR14A and LTR14B elements (Imbeault et al, 2017), suggesting a potential role in ERV silencing.…”

Dynamic Signatures of the Epigenome: Friend or Foe?

“…Interestingly, splicing variants of delta DNMT3B were also shown to confer DNA hypermethylation within specific genomic locations; however, the exact molecular mechanisms for such selectivity remain unknown [156]. Another hypothetical mechanism for targeted TSG hypermethylation may depend on KRAB-ZNF factors associated with particular cancers [157,158]. As it was mentioned previously, KRAB-ZNFs bind to specific DNA sequences and mediate deposition of repressive H3K9me3 mark, histone deacetylation, and in ESCs-mitotically heritable DNA methylation [159].…”

“…As it was mentioned previously, KRAB-ZNFs bind to specific DNA sequences and mediate deposition of repressive H3K9me3 mark, histone deacetylation, and in ESCs-mitotically heritable DNA methylation [159]. While the expression of multiple KRAB-ZNFs becomes deregulated in various tumors [157,158], it remains to be tested whether KRAB-ZNFs may also participate in the sequence-specific DNA hypermethylation, particularly in the cells with stem cell-like phenotype.…”