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.
Highlights
Hepatocellular carcinoma (HCC) is a primary malignant tumor that arises from the hepatocytes
We found that PATZ1 modulates liver cancer cell proliferation by regulating CDKN1B, a key cyclindependent kinase inhibitor
We examined mRNA and protein levels of PATZ1 in normal hepatocytes and liver cancer cell lines
Summary
Hepatocellular carcinoma (HCC) is a primary malignant tumor that arises from the hepatocytes. Chronic infection with hepatitis B (HBV) and C viruses (HCV) is responsible for 75% of all primary HCC cases worldwide, with a higher incidence in developing. The pathogenesis of HCC arising from HBV and HCV infection begins with proliferation and apoptosis, followed by inflammation, fibrosis, cirrhosis and dysplasia (Ananthakrishnan et al, 2006). Another well-characterized risk factor of HCC, leads to the development of primary liver cancer via cirrhosis (Chacko and Samanta, 2016). HCC is associated with non-alcoholic liver fatty disease (NAFLD), which is the hepatic manifestation of obesity and related metabolic disorders (Inayat et al, 2016). In NAFLD, accumulation of fat in the liver results in inflammation, leading to cirrhosis and eventually HCC (Chacko and Samanta, 2016). Cirrhosis is regarded as the most important risk factor for the development and progression of HCC regardless of its etiologies, with 90% of all HCC cases being accompanied by cirrhosis in the western hemisphere (El-Serag, 2011)
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