PATZ1 is a target of miR-29b that is induced by Ha-Ras oncogene in rat thyroid cells

Abstract

The regulatory transcriptional factor PATZ1 is constantly downregulated in human thyroid cancer where it acts as a tumour suppressor by targeting p53-dependent genes involved in Epithelial-Mesenchymal Transition and cell migration. The aim of the present work was to elucidate the upstream signalling mechanisms regulating PATZ1 expression in thyroid cancer cells. The bioinformatics search for microRNAs able to potentially target PATZ1 led to the identification of several miRNAs. Among them we focused on the miR-29b since it was found upregulated in rat thyroid differentiated cells transformed by the Ha-Ras oncogene towards a high proliferating and high migratory phenotype resembling that of anaplastic carcinomas. Functional assays confirmed PATZ1 as a target of miR-29b, and, consistently, an inverse correlation between miR-29b and PATZ1 protein levels was found upon induction of Ha-Ras oncogene expression in these cells. Interestingly, restoration of PATZ1 expression in rat thyroid cells stably expressing the Ha-Ras oncogene decreased cell proliferation and migration, indicating a key role of PATZ1 in Ras-driven thyroid transformation. Together, these results suggest a novel mechanism regulating PATZ1 expression based on the upregulation of miR-29b expression induced by Ras oncogene.

PATZ1 is a new prognostic marker of glioblastoma associated with the stem-like phenotype and enriched in the proneural subtype

“…These observations were validated and completed in independent glioma datasets, finding a significant overlap of high PATZ1 expression with the proneural subtype and conversely of low PATZ1 expression with the mesenchymal subtype in both GBMs and GSCs. Since PATZ1 has been described as an inhibitor of cell proliferation in some cancer cell contexts [ 13 , 20 , 39 ], we would expect that GSCs growing as spheres that express higher levels of PATZ1 compared to GSCs growing in adhesion may proliferate less. However, since there are no differences in the proliferation rate between GSCs growing as spheres and those growing as adherent cells [ 26 ], we concluded that PATZ1 is not associated with proliferation in these cells.…”

Structural analysis of the PATZ1 BTB domain homodimer

“…A role for PATZ1 has been demonstrated in various malignancies such as thyroid and testicular cancer (Fedele et al, 2008(Fedele et al, , 2017Valentino, Palmieri, Vitiello, Pierantoni et al, 2013;Chiappetta et al, 2015;Vitiello et al, 2016;Monaco et al, 2018). The interaction between PATZ1 and the tumour suppressor p53 (Valentino, Palmieri, Vitiello, Pierantoni et al, 2013;Valentino, Palmieri, Vitiello, Simeone et al, 2013;Chiappetta et al, 2015;Keskin et al, 2015) mediated by a motif in the zinc-finger DNA-binding domain rather than the BTB domain also links this protein to cancer.…”

The POZ/BTB and AT-Hook Containing Zinc Finger 1 (PATZ1) Transcription Regulator: Physiological Functions and Disease Involvement

“…Downregulation of PATZ1 expression in thyroid cancer cells has been associated with the activation of the Ras signaling, which leads to overexpression of miR-29b that, in turn, targets and downregulates PATZ1 [ 19 ]. However, in thyroid cancer PATZ1 protein is not only downregulated compared to normal thyroid tissue, but it is also increasingly delocalized from the nucleus to the cytoplasm proceeding from differentiated to undifferentiated thyroid carcinomas [ 40 ].…”

“…Only few studies have so far analyzed how PATZ1 expression is regulated. Two of them have focused on its post-transcriptional regulation by microRNAs, showing that miR-29b and miR-24 are specific inhibitors of PATZ1 expression [ 19 , 20 ]. Another study, performed in mouse embryonic stem cells (ESC), demonstrated by ChIP experiments that Oct4 and Nanog pluripotent transcription factors bind to the proximal promoter and the first intron of Patz1 , respectively, suggesting that Patz1 is a downstream target of Oct4 and Nanog [ 21 ].…”