Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou, China.
Cancer Res. 2020 Oct 1;80(19):4114-4128. doi: 10.1158/0008-5472.CAN-20-0493. Epub 2020 Jul 10.
Copy number gain in chromosome 8q21 is frequently detected in breast cancer, yet the oncogenic potential underlying this amplicon in breast carcinogenesis remains to be delineated. We report here that ZNF704, a gene mapped to 8q21, is recurrently amplified in various malignancies including breast cancer. ZNF704 acted as a transcriptional repressor and interacted with the transcriptional corepressor SIN3A complex. Genome-wide interrogation of transcriptional targets revealed that the ZNF704/SIN3A complex represses a panel of genes including PER2 that are critically involved in the function of the circadian clock. Overexpression of ZNF704 prolonged the period and dampened the amplitude of the circadian clock. ZNF704 promoted the proliferation and invasion of breast cancer cells and accelerated the growth and metastasis of breast cancer . Consistently, the level of ZNF704 expression inversely correlated with that of PER2 in breast carcinomas, and high level of ZNF704 correlated with advanced histologic grades, lymph node positivity, and poor prognosis of patients with breast cancer, especially those with HER2 and basal-like subtypes. These results indicate that ZNF704 is an important regulator of the circadian clock and a potential driver for breast carcinogenesis. SIGNIFICANCE: This study indicates that ZNF704 could be a potential oncogenic factor, disrupting circadian rhythm of breast cancer cells and contributing to breast carcinogenesis.
8q21 染色体上的拷贝数增益在乳腺癌中经常被检测到，但该扩增子在乳腺癌发生中的致癌潜力仍有待阐明。我们在这里报告，ZNF704 是一个定位于 8q21 的基因，在包括乳腺癌在内的各种恶性肿瘤中经常被扩增。ZNF704 作为转录抑制剂，与转录共抑制因子 SIN3A 复合物相互作用。对转录靶标的全基因组研究揭示，ZNF704/SIN3A 复合物抑制一组基因，包括 PER2，这些基因在生物钟功能中起着至关重要的作用。ZNF704 的过表达延长了生物钟的周期并减弱了振幅。ZNF704 促进乳腺癌细胞的增殖和侵袭，并加速乳腺癌的生长和转移。一致地，ZNF704 在乳腺癌中的表达水平与 PER2 的表达水平呈负相关，高水平的 ZNF704 与高级别组织学、淋巴结阳性和乳腺癌患者的不良预后相关，尤其是与 HER2 和基底样亚型相关。这些结果表明，ZNF704 是生物钟的重要调节因子，也是乳腺癌发生的潜在驱动因素。意义：本研究表明，ZNF704 可能是一种潜在的致癌因子，破坏乳腺癌细胞的昼夜节律，促进乳腺癌的发生。
