POZ-, AT-hook-, and Zinc Finger-containing Protein (PATZ) Interacts with Human Oncogene B Cell Lymphoma 6 (BCL6) and Is Required for Its Negative Autoregulation

Pero, Raffaela; Palmieri, Dario; Angrisano, Tiziana; Valentino, Teresa; Federico, Antonella; Franco, Renato; Lembo, Francesca; Klein‐Szanto, Andres J.; Vecchio, Luigi Del; Montanaro, Donatella; Keller, Simona; Arra, Claudio; Papadopoulou, Vasiliki; Wagner, Simon D.; Croce, Carlo M.; Chiariotti, Lorenzo; Fedele, Monica

doi:10.1074/jbc.m112.346270

Cited by 16 publications

(26 citation statements)

References 37 publications

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“…Similarly, we previously demonstrated that PATZ1 is overexpressed in testicular tumors, but protein localized into the cytoplasm rather than into the nucleus, suggesting a reduction of its transcriptional function [21]. Recently, we showed that PATZ1-knockout mice develop lymphomas and other neoplasias, indicating PATZ1 as a potential tumor-suppressor in lymphomagenesis and likely other tumors [17]. …”

Section: Introductionmentioning

confidence: 91%

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PATZ1 acts as a tumor suppressor in thyroid cancer via targeting p53-dependent genes involved in EMT and cell migration

et al. 2015

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PATZ1, a POZ-Zinc finger protein, is emerging as an important regulator of development and cancer, but its cancer-related function as oncogene or tumor-suppressor is still debated. Here, we investigated its possible role in thyroid carcinogenesis. We demonstrated PATZ1 is down-regulated in thyroid carcinomas compared to normal thyroid tissues, with an inverse correlation to the degree of cell differentiation. In fact, PATZ1 expression was significantly further down-regulated in poorly differentiated and anaplastic thyroid cancers compared to the papillary histotype, and it resulted increasingly delocalized from the nucleus to the cytoplasm proceeding from differentiated to undifferentiated thyroid carcinomas. Restoration of PATZ1 expression in three thyroid cancer-derived cell lines, all characterized by fully dedifferentiated cells, significantly inhibited their malignant behaviors, including in vitro proliferation, anchorage-independent growth, migration and invasion, as well as in vivo tumor growth. Consistent with recent studies showing a role for PATZ1 in the p53 pathway, we showed that ectopic expression of PATZ1 in thyroid cancer cells activates p53-dependent pathways opposing epithelial-mesenchymal transition and cell migration to prevent invasiveness. These results provide insights into a potential tumor-suppressor role of PATZ1 in thyroid cancer progression, and thus may have potential clinical relevance for the prognosis and therapy of thyroid cancer.

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Section: Introductionmentioning

confidence: 91%

“…PATZ1 has been demonstrated to regulate, either positively or negatively, the expression of different genes depending on the cellular context [11–17]. …”

Section: Introductionmentioning

confidence: 99%

PATZ1 acts as a tumor suppressor in thyroid cancer via targeting p53-dependent genes involved in EMT and cell migration

et al. 2015

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“…Previous results from our laboratory showed that Patz1-ko mice have enhanced susceptibility to spontaneously develop different tumors in advanced age, including B cell lymphomas, sarcomas, hepatocarcinomas and rare lung and thyroid adenocarcinomas [18]. Regarding B Cell lymphomas, we have shown that a critical mechanism for their development relies on the negative control that PATZ1 has on BCL6 gene transcription [18], a gene tightly associated with the development of B Cell lymphomas [19], and recently shown to be involved in EMT induction in breast cancer [20]. In a meta-analysis of public datasets (GOBO and TGCA), PATZ1 expression is significantly downregulated in basal (specifically basal B type) vs luminal breast tumors and vs normal breast.…”

Section: Introductionmentioning

confidence: 94%

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

Fedele

Cerchia²,

Chiappetta³

2016

Chemotherapy

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PATZ1 is a chromatin-regulating factor with emerging roles in stemness and cancer. It has been suggested to play a dual oncogene/tumor suppressor role depending on the cellular context, but its function in human tumor biology is still far to be completely elucidated. We have recently identified its tumor suppressive role in thyroid carcinogenesis, possibly through the association between PATZ1 and p53 to oppose epithelial-mesenchymal transition and cell migration. These are major processes in tumor progression, local invasion, metastasis, and therapeutic resistance and play a recognized role in the development of thyroid cancer, particularly anaplastic thyroid carcinoma, but many questions about how they are orchestrated remain opened. Elucidation of the mechanisms regulating epithelial-mesenchymal transition and cell migration can suggest new candidates for antimetastatic drug development that could lead to more effective therapies for highly aggressive and lethal thyroid cancers.

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“…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).…”

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confidence: 99%

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

Keskin

Deniz

Eryilmaz

et al. 2015

Molecular and Cellular Biology

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e Insults to cellular health cause p53 protein accumulation, and loss of p53 function leads to tumorigenesis. Thus, p53 has to be tightly controlled. Here we report that the BTB/POZ domain transcription factor PATZ1 (MAZR), previously known for its transcriptional suppressor functions in T lymphocytes, is a crucial regulator of p53. The novel role of PATZ1 as an inhibitor of the p53 protein marks its gene as a proto-oncogene. PATZ1-deficient cells have reduced proliferative capacity, which we assessed by transcriptome sequencing (RNA-Seq) and real-time cell growth rate analysis. PATZ1 modifies the expression of p53 target genes associated with cell proliferation gene ontology terms. Moreover, PATZ1 regulates several genes involved in cellular adhesion and morphogenesis. Significantly, treatment with the DNA damage-inducing drug doxorubicin results in the loss of the PATZ1 transcription factor as p53 accumulates. We find that PATZ1 binds to p53 and inhibits p53-dependent transcription activation. We examine the mechanism of this functional inhibitory interaction and demonstrate that PATZ1 excludes p53 from DNA binding. This study documents PATZ1 as a novel player in the p53 pathway. Wild-type (WT) p53 is a stress-responsive, sequence-specific transcription factor that inhibits the cell cycle, promotes senescence, and, if the insult to cellular health is not resolved, induces apoptotic death (1). p53 mutations that allow cells to escape this death are the most common genetic event in human cancer (2). Alternative mechanisms of escape rely on the overexpression of MDM2 and MDMX, major negative regulators of p53 that keep p53 levels low under unstressed conditions through ubiquitination-mediated degradation (3). Moreover, many DNA tumor viruses encode proteins that can inactivate p53 (2). However, the list of p53 regulators is far from complete. Various stress conditions result in the upregulation of p53, controlled by feedback loops, posttranslational modifications, and epigenetic changes. In the present study, we aimed to find new players that modify p53 function.p53 is composed of an N-terminal transactivation domain (through which it interacts with MDM2), a proline-rich domain, central DNA binding and tetramerization domains, and a C-terminal regulatory domain. p53 binds response elements (REs) in nuclear DNA, which results in stress-induced changes (either upor downregulation) in gene expression. Tetrameric p53 binds REs that are composed of two half-sites, each with a consensus of RR RCWWGYYY, separated by 0 to 21 bases (where R is a purine, Y is a pyrimidine, and W is either an A or T) (4). p53 REs can be subcategorized as those that respond to low levels of wild-type p53, those that respond to stabilized p53 after stress, and those that respond to p53 with mutations in its DNA binding domain. A recent study found 160 p53 REs controlling 129 genes in the human genome (5). Another study using chromatin immunoprecipitation (ChIP) with paired-end ditag (PET) sequencing identified 542 functional p53 binding sites...

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POZ-, AT-hook-, and Zinc Finger-containing Protein (PATZ) Interacts with Human Oncogene B Cell Lymphoma 6 (BCL6) and Is Required for Its Negative Autoregulation

Cited by 16 publications

References 37 publications

PATZ1 acts as a tumor suppressor in thyroid cancer via targeting p53-dependent genes involved in EMT and cell migration

PATZ1 acts as a tumor suppressor in thyroid cancer via targeting p53-dependent genes involved in EMT and cell migration

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

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

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