Abstract
Positive Regulatory Domain (PRDM) gene family members commonly express two main molecular variants, the PR-plus isoform usually acting as tumor suppressor and the PR-minus one functioning as oncogene. Accordingly, PRDM2/RIZ encodes for RIZ1 (PR-plus) and RIZ2 (PR-minus). In human cancers, genetic or epigenetic modifications induce RIZ1 silencing with an expression level imbalance in favor of RIZ2 that could be relevant for tumorigenesis. Additionally, in estrogen target cells and tissues, estradiol increases RIZ2 expression level with concurrent increase of cell proliferation and survival. Several attempts to study RIZ2 function in HeLa or MCF-7 cells by its over-expression were unsuccessful. Thus, we over-expressed RIZ2 in HEK-293 cells, which are both RIZ1 and RIZ2 positive but unresponsive to estrogens. The forced RIZ2 expression increased cell viability and growth, prompted the G2-to-M phase transition and organoids formation. Accordingly, microarray analysis revealed that RIZ2 regulates several genes involved in mitosis. Consistently, RIZ silencing in both estrogen-responsive MCF-7 and -unresponsive MDA-MB-231 cells induced a reduction of cell proliferation and an increase of apoptosis rate. Our findings add novel insights on the putative RIZ2 tumor-promoting functions, although additional attempts are warranted to depict the underlying molecular mechanism.
Highlights
PR/SET Domain 2 (PRDM2) or Retinoblastoma Interacting Zinc finger (RIZ) protein is a member of the Positive Regulatory Domain (PRDM) gene family, which encodes for 19 different transcription factors in humans [1,2,3]
The balance between RIZ1 and RIZ2 was modified in favor to RIZ2, reproducing a condition often observed in cancer [3, 8]
The RIZ2 overexpression was verified after transfection by qRT-PCR of reverse-transcribed total cellular RNA, using two sets of primers: 118F/438R and 649F/975R recognizing sequences on exons 3 and 5 or on exon 8 respectively in both transient and stable transfected cells (Figure S1 and Figure 1A) [34, 39]. qRT-PCR analysis revealed a highly significant increase of RIZ2 expression levels with a decrease in RIZ1 expression levels compared to control cells suggesting a putative mechanism of transcription autoregulation
Summary
PR/SET Domain 2 (PRDM2) or Retinoblastoma Interacting Zinc finger (RIZ) protein is a member of the Positive Regulatory Domain (PRDM) gene family, which encodes for 19 different transcription factors in humans [1,2,3]. All PRDM family members share an evolutionary conserved N-terminal domain, known as PR domain (PRDI-BF1-RIZ1 homologous), structurally and functionally similar to the SET domain (Su(var), Enhancer-of-zeste and Trithorax) [4,5,6,7]. PRDM proteins function by tethering transcription factors to target gene promoters or by recognition of specific DNA consensus sequences via the Zinc-finger domains [6, 7]. PRDM proteins contribute to many developmental processes, driving cell proliferation, differentiation, and maturation events by specifying cell fate choice or maintaining cell specialization through transduction of several cell signals [3, 4, 6]
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