PATZ1 (MAZR) Co-occupies Genomic Sites With p53 and Inhibits Liver Cancer Cell Proliferation via Regulating p27

Abstract

Liver cancer is the third most common cause of cancer death in the world. POZ/BTB and AT-hook-containing zinc finger protein 1 (PATZ1/MAZR) is a transcription factor associated with various cancers. However, the role of PATZ1 in cancer progression remains controversial largely due to lack of genome-wide studies. Here we report that PATZ1 regulates cell proliferation by directly regulating CDKN1B (p27) in hepatocellular carcinoma cells. Our PATZ1 ChIP-seq and gene expression microarray analyses revealed that PATZ1 is strongly related to cancer signatures and cellular proliferation. We further discovered that PATZ1 depletion led to an increased rate of colony formation, elevated Ki-67 expression and greater S phase entry. Importantly, the increased cancer cell proliferation was accompanied with suppressed expression of the cyclin-dependent kinase inhibitor CDKN1B. Consistently, we found that PATZ1 binds to the genomic loci flanking the transcriptional start site of CDKN1B and positively regulates its transcription. Notably, we demonstrated that PATZ1 is a p53 partner and p53 is essential for CDKN1B regulation. In conclusion, our study provides novel mechanistic insights into the inhibitory role of PATZ1 in liver cancer progression, thereby yielding a promising therapeutic intervention to alleviate tumor burden.

POZ/BTB and AT hook containing zinc finger 1 (PATZ1) suppresses differentiation and regulates metabolism in human embryonic stem cells

“…We accordingly figured out the consolidated PATZ1 motif which was enriched with GC fragments. The conserved motif in human ESCs were consistent with previous studies by our laboratory 22 , 27 . The high affinity to cytosine and guanine shall be attributed to the two AT-hook domains in the central region, and a C2H2-ZF domain at the C-terminal in PATZ1 19 .…”

“…The diversity of domains allows PATZ1 to play multiple roles in gene regulation. Tumor suppressive role of PATZ1 has been found in thyroid cancer cells [23][24][25], testicular germ cells [26] and liver cancer cells [27]. Conversely, PATZ1 may act as an oncogene because it promotes the cell cycle in colon cancer [28].…”

PATZ1 in Non-Small Cell Lung Cancer: A New Biomarker That Negatively Correlates with PD-L1 Expression and Suppresses the Malignant Phenotype

“…Consistently, Patz1 +/− mouse embryonic fibroblasts display epigenetic histone modifications characteristic of transcriptionally active chromatin [ 13 ]. PATZ1 expression is strongly related to cancer signatures and cellular proliferation, as recently assessed by PATZ1 ChIP-seq and gene expression microarray analyses [ 14 ]. Indeed, it has been shown to act as an oncogene in colon cancer and glioblastoma cells [ 15 , 16 , 17 , 18 ] and a tumor suppressor in glioblastoma [ 19 ], thyroid [ 20 , 21 , 22 ], ovarian [ 23 ], and liver cancer cells [ 14 ].…”

“…PATZ1 expression is strongly related to cancer signatures and cellular proliferation, as recently assessed by PATZ1 ChIP-seq and gene expression microarray analyses [ 14 ]. Indeed, it has been shown to act as an oncogene in colon cancer and glioblastoma cells [ 15 , 16 , 17 , 18 ] and a tumor suppressor in glioblastoma [ 19 ], thyroid [ 20 , 21 , 22 ], ovarian [ 23 ], and liver cancer cells [ 14 ]. Additionally, PATZ1 has been proposed as a diagnostic/prognostic biomarker in different neoplasia, including testicular germ cell tumors [ 24 ], renal cell carcinoma [ 25 , 26 , 27 ], CNS neoplasms [ 28 , 29 , 30 ], round cell sarcomas [ 31 ], large cell B lymphomas [ 32 ], thyroid cancer [ 20 ], and ovarian cancer [ 23 ], where lower levels and cytoplasmic localization of the PATZ1 protein are often predictive of a more aggressive phenotype and, consequently, the worst prognosis [ 20 , 23 , 28 , 32 ].…”