Circadian Rhythm Is Disrupted by ZNF704 in Breast Carcinogenesis

Abstract

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 in vitro and accelerated the growth and metastasis of breast cancer in vivo. 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.