Ng Zhen Long, Siew Jiamin, Li Jia, Ji Guanxu, Huang Min, Liao Xiaohua, Yu Sue, Chew Yuanyuan, Png Chin Wen, Zhang Yongliang, Wen Shijun, Yang Henry, Zhou Yiting, Long Yun Chau, Jiang Zhi Hong, Wu Qiang
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
Cancer Science Institute of Singapore, Centre for Translational Medicine, Singapore, Singapore.
Front Cell Dev Biol. 2021 Feb 1;9:586150. doi: 10.3389/fcell.2021.586150. eCollection 2021.
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 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.
肝癌是全球第三大常见癌症死因。含POZ/BTB和AT钩的锌指蛋白1（PATZ1/MAZR）是一种与多种癌症相关的转录因子。然而，由于缺乏全基因组研究，PATZ1在癌症进展中的作用仍存在争议。在此，我们报告PATZ1通过直接调控肝癌细胞中的CDKN1B（p27）来调节细胞增殖。我们的PATZ1染色质免疫沉淀测序（ChIP-seq）和基因表达微阵列分析表明，PATZ1与癌症特征和细胞增殖密切相关。我们进一步发现，PATZ1缺失导致集落形成率增加、Ki-67表达升高以及S期进入增加。重要的是，癌细胞增殖增加伴随着细胞周期蛋白依赖性激酶抑制剂CDKN1B的表达受抑制。一致地，我们发现PATZ1与CDKN1B转录起始位点侧翼的基因组位点结合，并正向调节其转录。值得注意的是，我们证明PATZ1是p53的伙伴，且p53对CDKN1B的调节至关重要。总之，我们的研究为PATZ1在肝癌进展中的抑制作用提供了新的机制见解，从而为减轻肿瘤负担提供了一种有前景的治疗干预措施。
