Theranostics 2019; 9(26):8182-8195. doi:10.7150/thno.34983

Research Paper

Tumor suppressive BTB/POZ zinc-finger protein ZBTB28 inhibits oncogenic BCL6/ZBTB27 signaling to maintain p53 transcription in multiple carcinogenesis

Tingxiu Xiang1, Jun Tang1, Lili Li2, Weiyan Peng1, Zhenfang Du2, Xiangyu Wang2, Qianqian Li1, Hongying Xu1, Lei Xiong2, Can Xu1, Xin Le1, Xufu Wei1, Fang Yu1, Shuman Li1, Qian Xiao1, Bing Luo3, Xinni Xiang1, Ailong Huang4, Yong Lin5, Guosheng Ren1✉, Qian Tao1,2✉

1. Key Laboratory of Molecular Oncology and Epigenetics, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China;
2. Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Translational Oncology, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong;
3. Department of Medical Microbiology, Qingdao University Medical College, China;
4. MOE Key Laboratory of Molecular Biology for Infectious Diseases, Department of Infectious Disease, Chongqing Medical University, China;
5. Lovelace Respiratory Research Institute, Albuquerque, New Mexico, USA

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Citation:
Xiang T, Tang J, Li L, Peng W, Du Z, Wang X, Li Q, Xu H, Xiong L, Xu C, Le X, Wei X, Yu F, Li S, Xiao Q, Luo B, Xiang X, Huang A, Lin Y, Ren G, Tao Q. Tumor suppressive BTB/POZ zinc-finger protein ZBTB28 inhibits oncogenic BCL6/ZBTB27 signaling to maintain p53 transcription in multiple carcinogenesis. Theranostics 2019; 9(26):8182-8195. doi:10.7150/thno.34983. Available from http://www.thno.org/v09p8182.htm

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Abstract

Zinc-finger and BTB/POZ domain-containing family proteins (ZBTB) are important transcription factors functioning as tumor suppressors or oncogenes, such as BCL6/ZBTB27 as a key oncoprotein for anti-cancer therapy. Through epigenome study, we identified ZBTB28/BCL6B/BAZF, a BTB/POZ domain protein highly homologous to BCL6, as a methylated target in multiple tumors. However, the functions and mechanism of ZBTB28 in carcinogenesis remain unclear. Methods: ZBTB28 expression and methylation were examined by reverse-transcription PCR and methylation-specific PCR. The effects and mechanisms of ectopic ZBTB28 expression on tumor cells were assessed with molecular biological and cellular approaches in vitro and in vivo. Results: Albeit broadly expressed in multiple normal tissues, ZBTB28 is frequently downregulated in aero- and digestive carcinoma cell lines and primary tumors, and correlated with its promoter CpG methylation status. Further gain-of-function study showed that ZBTB28 functions as a tumor suppressor inhibiting carcinoma cell growth in vitro and in vivo, through inducing cell cycle arrest and apoptosis of tumor cells. ZBTB28 suppresses cell migration and invasion by reversing EMT and cell stemness. ZBTB28 transactivates TP53 expression, through binding to the p53 promoter in competition with BCL6, while BCL6 itself was also found to be a direct target repressed by ZBTB28. Conclusion: Our results demonstrate that ZBTB28 functions as a tumor suppressor through competing with BCL6 for targeting p53 regulation. This newly identified ZBTB28/BCL6/p53 regulatory axis provides further molecular insight into carcinogenesis mechanisms and has implications in further improving BCL6-based anticancer therapy.

Keywords: ZBTB28, CpG methylation, BCL6, p53, zinc finger protein