Knockdown of ZBTB7A inhibits cell proliferation of breast cancer through regulating the ubiquitination of estrogen receptor alpha

Aims ZBTB7A, a transcriptional repressor, accelerates the breast cancer progression. Over 70% of breast cancer samples are identified as ER-α positive. Due to the function of ZBTB7A in ER-α positive breast cancer incompletely known, we aimed to determine the role of ZBTB7A in ER-α positive cancer and explore the underlying mechanisms. Main methods In this study, the correlation between ZBTB7A and ER-α was confirmed by tissue microarray-based and TCGA database. Then, we explore if ZBTB7A maintains ER-α′s level via targeting ER-α′s expression or degradation. Finally, we examined the effect of ZBTB7A on the proliferation of breast cancer cells. Key findings We further confirmed that ZBTB7A shows a significant positive correlation with ER-α in clinical breast cancer samples by tissue microarray-based analysis. Mechanically, we identified that the inhibition of ZBTB7A could upregulate E3 ligase TRIM25 leading to enhancement of ER-α ubiquitination and proteasomal degradation, which could partly explain the correlation between ZBTB7A and ER-α. Besides, we uncovered that ZBTB7A could also transcriptionally increase the expression of ER-α via indirectly binding to the region +146 to +461 bp downstream of the transcription start site of ESR1 (ERpro315) in breast cancer cells. Furthermore, ZBTB7A is found to stimulate the expression of ER-α′s downstream genes, and promote the growth of estrogen receptor alpha (ER-α)-positive breast cancer cells. Significance Our data revealed the novel mechanisms through which ZBTB7A manipulates ER-α level and might provide a new avenue for endocrine therapy in breast cancer.