Myeloid Zinc Finger 1 and GA Binding Protein Co-Operate with Sox2 in Regulating the Expression of Yes-Associated Protein 1 in Cancer Cells

Abstract

The transcription factor (TF) yes-associated protein 1 (YAP1) is a major effector of the tumor suppressive Hippo signaling pathway and is also necessary to maintain pluripotency in embryonic stem cells. Elevated levels of YAP1 expression antagonize the tumor suppressive effects of the Hippo pathway that normally represses YAP1 function. High YAP1 expression is observed in several types of human cancers and is particularly prominent in cancer stem cells (CSCs). The stem cell TF Sox2, which marks and maintains CSCs in osteosarcomas (OSs), promotes YAP1 expression by binding to an intronic enhancer element and YAP1 expression is also crucial for the maintainance of OS stem cells. To further understand the regulation of YAP1 expression in OSs, we subjected the YAP1 intronic enhancer to scanning mutagenesis to identify all DNA cis-elements critical for enhancer function. Through this approach, we identified two novel TFs, GA binding protein (GABP) and myeloid zinc finger 1 (MZF1), which are essential for basal YAP1 transcription. These factors are highly expressed in OSs and bind to distinct sites in the YAP1 enhancer. Depletion of either factor leads to drastically reduced YAP1 expression and thus a reversal of stem cell properties. We also found that YAP1 can regulate the expression of Sox2 by binding to two distinct DNA binding sites upstream and downstream of the Sox2 gene. Thus, Sox2 and YAP1 reinforce each others expression to maintain stemness and tumorigenicity in OSs, but the activity of MZF1 and GABP is essential for YAP1 transcription. Stem Cells 2017;35:2340-2350.

The Hippo effector TAZ promotes cancer stemness by transcriptional activation of SOX2 in head neck squamous cell carcinoma

“…Subsequently, our results from luciferase reporter assays involving SOX2 promoter and its mutant as well as ChIP assays further confirmed the direct binding between TAZ/TEAD4 and SOX2 promoter in HNSCC. Noticeably, TAED binding sites in SOX2 promoter identified here were different from those found in other reports whereby two putative YAP/TEAD binding sites were found at upstream (−3759) and downstream ( + 5313) of SOX2 transcription start site (TSS) in murine osteosarcoma cells 35 . We reasoned that it’s conceivable that binding sites for transcriptional factors vary in diverse cell types and biological settings.…”

MZF1 and SCAND1 Reciprocally Regulate CDC37 Gene Expression in Prostate Cancer

“…These data suggest mechanisms whereby members of the SCAN transcription factor family can fine-tune prostate cancer growth by up or downregulating CDC37 transcription and thus decide the outcome of prostate tumorigenesis. It is likely that other MZF1 targets important in tumorigenesis may be regulated in a similar way [17], including oncogenes and pro-tumorigenic genes such as MYC [21], NCAD [31], YAP1 [32], TGF-beta [20], CTSB/L [33], MMP-14 [34], FOXM1 [35], CK17 [36], PAX2 [25], PRAME [24], DR5 [37], AXL [26,38], PKC-alpha [39,40], CD34 , and c-Myb [18]. Besides, MZF1 might play key roles also in tumor microenvironment such as mesenchymal stem cell differentiation into cancer-associated fibroblasts [20].…”

Transcription Factor Myeloid Zinc-Finger 1 Suppresses Human Gastric Carcinogenesis by Interacting with Metallothionein 2A

“…embryogenesis (21,22,26). Because initial studies of the role of MZF1 in myeloid differentiation and leukemia (18,23), it has been demonstrated that the MZF1-dependent transcriptional changes occur in malignant cellular processes (24,27,28,30,(36)(37)(38)(39)(40)(41)(42)(43), and aberrant expression of MZF1 correlates with poor prognosis of several types of cancers (29,32,34,44,45). However, the contribution of MZF1 to tumorigenesis has not been fully elucidated (20).…”