Zinc finger and SCAN domain containing 1, ZSCAN1, is a novel stemness-related tumor suppressor and transcriptional repressor in breast cancer targeting TAZ

Abstract

IntroductionCancer stem cells (CSCs) targeted therapy holds the potential for improving cancer management; identification of stemness-related genes in CSCs is necessary for its development.MethodsThe Cancer Genome Atlas (TCGA) and the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) datasets were used for survival analysis. ZSCAN1 correlated genes was identified by Spearman correlation analysis. Breast cancer stem-like cells (BCSLCs) were isolated by sorting CD44+CD24- cells from suspension cultured breast cancer (BC) spheroids. The sphere-forming capacity and sphere- and tumor-initiating capacities were determined by sphere formation and limiting dilution assays. The relative gene expression was determined by qRT-PCR, western blot. Lentivirus system was used for gene manipulation. Nuclear run-on assay was employed to examine the levels of nascent mRNAs. DNA pull-down and Chromatin immunoprecipitation (ChIP) assays were used for determining the interaction between protein and target DNA fragments. Luciferase reporter assay was used for evaluating the activity of the promoter.Results and discussionZSCAN1 is aberrantly suppressed in BC, and this suppression indicates a bad prognosis. Ectopic expression of ZSCAN1 inhibited the proliferation, clonogenicity, and tumorigenicity of BC cells. ZSCAN1-overexpressing BCSLCs exhibited weakened stemness properties. Normal human mammary epithelial (HMLE) cells with ZSCAN1 depletion exhibited enhanced stemness properties. Mechanistic studies showed that ZSCAN1 directly binds to -951 ~ -925bp region of WWTR1 (encodes TAZ) promoter, inhibits WWTR1 transcription, thereby inhibiting the stemness of BCSCs. Our work thus revealed ZSCAN1 as a novel stemness-related tumor suppressor and transcriptional repressor in BC.

High-Titer Anti-ZSCAN1 Antibodies in a Toddler Clinically Diagnosed with Apparent Rapid-Onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation Syndrome

“…In recent years, a number of reports link the high methylation and/or low expression levels of the ZSCAN1 gene to proliferation in cervical and breast cancers [ 43 , 44 ]. In breast cancer, ZSCAN1 acts as a tumor suppressor by inhibiting TAZ, which is a component of the Hippo (YAP/TAZ) pathway, an intracellular signaling network, the deregulation of which is known to promote tumor growth [ 45 ]. Some researchers hypothesize that the Hippo pathway could be involved in the metastasis of neuroblastoma [ 46 ].…”

Hsa_circ_0007823 Overexpression Suppresses the Progression of Triple-Negative Breast Cancer via Regulating miR-182-5p-FOXO1 Axis

“… 2 Luminal breast cancer, the most common subtype, has the best prognosis and benefits from targeted endocrine therapy due to hormone receptor expression as well as HER2-amplified breast cancer benefits from anti-HER2 therapy. 3 However, TNBC is a biologically and clinically heterogeneous disease that differs from other subtypes, TNBC develops metastases earlier after diagnosis, with higher brain, liver, and lung metastasis rates, and relatively poor outcomes and prognosis. 4 Endocrine therapy, molecular-targeted therapy, and chemotherapy, which are effective for other subtypes, are not effective for treating TNBC, and standardized treatment protocols for TNBC are lacking.…”