PATZ1 interacts with p53 and regulates expression of p53-target genes enhancing apoptosis or cell survival based on the cellular context

Abstract

PATZ1 is a transcriptional factor functioning either as an activator or a repressor of gene transcription depending upon the cellular context. It appears to have a dual oncogenic/anti-oncogenic activity. Indeed, it is overexpressed in colon carcinomas, and its silencing inhibits colon cancer cell proliferation or increases sensitivity to apoptotic stimuli of glioma cells, suggesting an oncogenic role. Conversely, the development of B-cell lymphomas, sarcomas, hepatocellular carcinomas and lung adenomas in Patz1-knockout (ko) mice supports its tumour suppressor function. PATZ1 role in mouse lymphomagenesis is mainly because of the involvement of PATZ1 in BCL6-negative autoregulation. However, this does not exclude that PATZ1 may be involved in tumorigenesis by other mechanisms. Here, we report that PATZ1 interacts with the tumour suppressor p53 and binds p53-dependent gene promoters, including those of BAX, CDKN1A and MDM2. Knockdown of PATZ1 in HEK293 cells reduces promoter activity of these genes and inhibits their expression, suggesting a role of PATZ in enhancing p53 transcriptional activity. Consistently, Patz1-ko mouse embryonic fibroblasts (MEFs) show decreased expression of Bax, Cdkn1a and Mdm2 compared with wild-type (wt) MEFs. Moreover, Patz1-ko MEFs show a decreased percentage of apoptotic cells, either spontaneous or induced by treatment with 5-fluorouracil (5FU), compared with wt controls, suggesting a pro-apoptotic role for PATZ1 in these cells. However, PATZ1 binds p53-target genes also independently from p53, exerting, in the absence of p53, an opposite function on their expression. Indeed, knockdown of PATZ1 in p53-null osteosarcoma cells upregulates BAX expression and decreases survival of 5FU-treated cells, then suggesting an anti-apoptotic role of PATZ1 in p53-null cancer cells. Therefore, these data support a PATZ1 tumour-suppressive function based on its ability to enhance p53-dependent transcription and apoptosis. Conversely, its opposite and anti-apoptotic role in p53-null cancer cells provides the perspective of PATZ1 silencing as a possible adjuvant in the treatment of p53-null cancer.

The Tumor Suppressive Role of PATZ1 in Thyroid Cancer: A Matter of Epithelial-Mesenchymal Transition

“…Consistent with the ability of PATZ1 to interact with p53 and regulate transcription of p53 target genes [10,13], we next showed that in PATZ1-expressing cells the EMT and cell migration gene program, activated by EGF and negatively regulated by p53, was deregulated. In more details, PATZ1 binds the promoter regions of three genes, EpCam, RhoE and Caldesmon, involved in EMT, cellular migration and invasion, respectively, modulating their transcriptional changes associated with EGF stimulation (Figure 1).…”

“…The POZ-AT hook-Zinc finger (PATZ1) protein is a transcriptional regulatory factor that can either activate or downregulate gene expression depending on the cellular context [10]. It has been recently indicated as a "stemness factor" [11] and shown to play a critical role in reprogramming somatic cells into pluripotent stem cells [12].…”

“…It has been recently indicated as a "stemness factor" [11] and shown to play a critical role in reprogramming somatic cells into pluripotent stem cells [12]. PATZ1 expression is regulated by DNA damage [13] and appears deregulated in different human cancers, suggesting a cancer-related role [14][15][16][17], which appears oncogenic or anti-oncogenic depending on the tumor type and likely on the presence/absence of a wild-type p53 protein with which it interacts [10,13]. Consistently, silencing of PATZ1 expression in a p53-null osteosarcoma cell line enhanced its sensitivity to the proapoptotic chemotherapeutic agent 5-fluorouracil (5FU), while Patz1-/-mouse embryonic fibroblasts show a decreased number of apoptotic cells, either spontaneous or induced by 5FU treatment, compared with wild-type controls [10].…”

“…PATZ1 expression is regulated by DNA damage [13] and appears deregulated in different human cancers, suggesting a cancer-related role [14][15][16][17], which appears oncogenic or anti-oncogenic depending on the tumor type and likely on the presence/absence of a wild-type p53 protein with which it interacts [10,13]. Consistently, silencing of PATZ1 expression in a p53-null osteosarcoma cell line enhanced its sensitivity to the proapoptotic chemotherapeutic agent 5-fluorouracil (5FU), while Patz1-/-mouse embryonic fibroblasts show a decreased number of apoptotic cells, either spontaneous or induced by 5FU treatment, compared with wild-type controls [10]. However, in a colon cancer cell line, even in the presence of a wild-type p53, PATZ1 has been shown to inhibit p53 function [13], supporting the concept that PATZ1 may have opposite roles on p53 in different tumors.…”

PATZ1 Is a DNA Damage-Responsive Transcription Factor That Inhibits p53 Function

“…PATZ1 can interact with other BTB-ZF transcription factors such as BCL-6 and Bach to control important cell fate decisions (13,14). While PATZ1 was originally identified as a lymphocyte specific c-Myc-regulating transcription factor, its expression and function are not restricted only to T lymphocytes (15)(16)(17)(18)(19). Early embryonic expression is likely functional, as Patz1 Ϫ/Ϫ mice are born at a non-Mendelian frequency and are small in size (16,17).…”