Abstract
EGFR is required for animal development, and dysregulation of EGFR is critically implicated in malignant transformation. However, the molecular mechanism underlying the regulation of EGFR expression remains poorly explored. Here we report that the zinc-finger protein ZNF516 is a transcription repressor. ZNF516 is physically associated with the CtBP/LSD1/CoREST complex and transcriptionally represses a cohort of genes including EGFR that are critically involved in cell proliferation and motility. We demonstrate that the ZNF516–CtBP/LSD1/CoREST complex inhibits the proliferation and invasion of breast cancer cells in vitro and suppresses breast cancer growth and metastasis in vivo. Significantly, low expression of ZNF516 is positively associated with advanced pathological staging and poor survival of breast carcinomas. Our data indicate that ZNF516 is a transcription repressor and a potential suppressor of EGFR, adding to the understanding of EGFR-related breast carcinogenesis and supporting the pursuit of ZNF516 as a potential therapeutic target for breast cancer.
Highlights
Epidermal growth factor receptor (EGFR) is required for animal development, and dysregulation of EGFR is critically implicated in malignant transformation
We demonstrate that the Zinc-finger protein 516 (ZNF516) inhibits the proliferation and invasive potential of breast cancer cells in vitro and suppresses breast cancer growth and metastasis in vivo
It has been documented that amplifications in the EGFR gene are restricted to regions of the regulatory sequence in the 5′-end of intron 1 and associated with EGFR expression in epithelial breast tumors[14], suggesting that transcriptional regulation of EGFR might be pathologically relevant in breast cancer carcinogenesis by contributing to EGFR overexpression
Summary
EGFR is required for animal development, and dysregulation of EGFR is critically implicated in malignant transformation. EGFR overexpression has been reported in cancers originating from bladder, brain, breast, cervical, uterine, colon, esophageal, glioma, lung, ovarian, pancreatic, and renal cell[3,4,5,6,7], and this dysregulation is often associated with a more aggressive phenotype and worse survival of the cancer patients[8] This scenario makes the EGFR family an ideal target to be exploited for cancer therapeutics[9,10,11]. Despite the extensive molecular and functional characterization of EGFR and a continuing effort in pursuing anti-EGFR cancer therapies, the molecular mechanism underlying the regulation/dysregulation of EGFR expression remains poorly explored This issue is of particular importance as it was noted that amplifications in the EGFR gene are restricted to regions of the regulatory sequence in the 5′-end of intron 1 and associated with EGFR expression in epithelial breast tumors[14], implying the importance of transcriptional regulation of EGFR in breast carcinogenesis. It has been reported that CtBP functions as either tumor suppressor or promoter, depending on the context of its associated partners[38,39,40,41]
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