KRAB-ZFP Transcriptional Regulators Acting as Oncogenes and Tumor Suppressors: An Overview

Abstract

Krüppel-associated box zinc finger proteins (KRAB-ZFPs) constitute the largest family of transcriptional factors exerting co-repressor functions in mammalian cells. In general, KRAB-ZFPs have a dual structure. They may bind to specific DNA sequences via zinc finger motifs and recruit a repressive complex through the KRAB domain. Such a complex mediates histone deacetylation, trimethylation of histone 3 at lysine 9 (H3K9me3), and subsequent heterochromatization. Nevertheless, apart from their repressive role, KRAB-ZFPs may also co-activate gene transcription, likely through interaction with other factors implicated in transcriptional control. KRAB-ZFPs play essential roles in various biological processes, including development, imprinting, retroelement silencing, and carcinogenesis. Cancer cells possess multiple genomic, epigenomic, and transcriptomic aberrations. A growing number of data indicates that the expression of many KRAB-ZFPs is altered in several tumor types, in which they may act as oncogenes or tumor suppressors. Hereby, we review the available literature describing the oncogenic and suppressive roles of various KRAB-ZFPs in cancer. We focused on their association with the clinicopathological features and treatment response, as well as their influence on the cancer cell phenotype. Moreover, we summarized the identified upstream and downstream molecular mechanisms that may govern the functioning of KRAB-ZFPs in a cancer setting.

Keywords: KRAB-ZFPs; ZBRK1; ZFP57; ZKSCAN3; ZNF224; ZNF300; ZNF471; cancer; epigenetic repressor.

Figure 1

The structure of various Krüppel-associated box zinc finger proteins (KRAB-ZFP) factors and their composing domains. The diagram shows the structure of selected factors (based on the Uniprot database) containing a KRAB domain at the N-terminus and the variable number of zinc fingers at the C-terminus. A KRAB domain may consist of two boxes: KRAB-A and KRAB-B. In some of the KRAB-ZFPs, an additional “SRE-ZBP, CTfin51, AW-1 and Number 18 cDNA” (SCAN) or “domain of the unknown function” (DUF3669) may also be present.

Figure 2

Repressive complex with the participation of a KRAB-ZFP factor. The repression complex contains the scaffold protein KAP1, H3K9 methyltransferase SET Domain Bifurcated 1 (SETDB1), heterochromatin protein 1 (HP1), and repressive Nucleosome Remodeling Deacetylase (NuRD) complex with Mi2α histone deacetylase. In certain cell types, the complex may also interact with DNA methyltransferase. These protein partners cooperatively inhibit transcriptional activity and promoter heterochromatization of the locus recognized by the zinc finger domain within an interacting KRAB-ZFP factor. A—histone acetylation, M—H3K9me3, white circles—unmethylated cytosines, black circles—methylated cytosines.

Figure 3

The involvement of ZFP57 and ZFP445 in gene imprinting. Both ZFP57 and ZNF445 are involved in maintaining methylation patterns by recruiting KAP1, DNA methyltransferase DNMT1, and histone methyltransferase SETDB1 to induce H3K9 trimethylation. The methylated imprinting control regions (ICR) on the top (black circles), unmethylated ICR on the bottom (white circles).

Figure 4

KRAB-ZFPs oncogene and tumor suppressor genes (TSG) role in the cancers of various tissue origins. The scheme presents the localization of different cancers in the human body, in which KRAB-ZFP factors may act as oncogenes (red font, the gene is upregulated) or tumor suppressor genes (green font, the gene is downregulated). Abbreviations: BLCA—bladder cancer, BRCA—breast cancer, CAA—cholangiocarcinoma, CESC—cervical cancer, CLL—chronic lymphocytic leukemia, CRC—colorectal cancer, EC—endometrial cancer, ESCC—esophageal squamous-cell carcinoma, GBM—glioblastoma, HCC—hepatocellular carcinoma, LUC—lung cancer, MM—multiple myeloma, OD—oligodendroglioma; OvCa—ovarian cancer, PAAD—pancreatic cancer, PRAD—prostate adenocarcinoma, RCC—kidney cancer, SC—skin cancer, SKCM—melanoma, STAD—gastric cancer, THCA—thyroid cancer.

Figure 5

The influence of selected KRAB-ZFPs on cell cycle. The KRAB-ZFP factors may induce cell cycle arrest (red arrows) or promote phase transition (green arrows) in a given phase. Abbreviations: KD—knockdown, OE—overexpression, AEL—acute erythroid leukemia, BRCA—breast cancer, CESC—cervical cancer, CLL—chronic lymphocytic leukemia, CRC—colorectal cancer, ESCC—esophageal squamous-cell carcinoma, HCC—hepatocellular carcinoma, NSCLC—non-small cell lung cancer, OvCa—ovarian cancer, STAD—gastric cancer.

Figure 6

An influence of selected KRAB-ZFP TSGs (A) and oncogenes (B) on various cancer-related signaling pathways and phenotypic features in neoplastic cells. The schematic representation demonstrates selected KRAB-ZFPs with oncogenic and TSG properties and their impact on the cellular signaling, apoptosis, response to treatment, proliferation, migration, and invasion of cancer cells, as well as patient survival. Some signaling pathways are yet to be understood. Green arrow—induction, red—inhibition, P—phosphorylation.