ZFP226 is a novel artificial transcription factor for selective activation of tumor suppressor KIBRA

Context: ZIC1 has been reported to be overexpressed and plays an oncogenic role in some brain tumors, whereas it is inactivated by promoter hypermethylation and acts as a tumor suppressor in gastric and colorectal cancers. However, until now, its biological role in thyroid cancer remains totally unknown. Objectives: The aim of this study is to explore the biological functions and related molecular mechanism of ZIC1 in thyroid carcinogenesis. Setting and Design: Quantitative RT-PCR (qRT-PCR) was performed to evaluate mRNA expression of investigated genes. Methylation-specific PCR was used to analyze promoter methylation of the ZIC1 gene. The functions of ectopic ZIC1 expression in thyroid cancer cells were determined by cell proliferation and colony formation, cell cycle and apoptosis, as well as cell migration and invasion assays. Results: ZIC1 was frequently down-regulated by promoter hypermethylation in both primary thyroid cancer tissues and thyroid cancer cell lines. Moreover, our data showed that ZIC1 hypermethylation was significantly associated with lymph node metastasis in patients with papillary thyroid cancer. Notably, restoration of ZIC1 expression in thyroid cancer cells dramatically inhibited cell proliferation, colony formation, migration and invasion, and induced cell cycle arrest and apoptosis by blocking the activities of the phosphatidylinositol-3-kinase (PI3K)/Akt and RAS/RAF/MEK/ERK (MAPK) pathways, and enhancing FOXO3a transcriptional activity. Conclusions: Our data demonstrate that ZIC1 is frequently inactivated by promoter hypermethyaltion and functions as a tumor suppressor in thyroid cancer through modulating PI3K/Akt and MAPK signaling pathways and transcription factor FOXO3a.

Download Full-text

Creation of a Six-fingered Artificial Transcription Factor That Represses the Hepatitis B Virus HBx Gene Integrated into a Human Hepatocellular Carcinoma Cell Line

CrossRef Listing of Deleted DOIs ◽

10.1177/1087057112463066 ◽

2012 ◽

Vol 18 (4) ◽

pp. 378-387 ◽

Cited By ~ 7

Author(s):

Xinghui Zhao ◽

Zhanzhong Zhao ◽

Junwei Guo ◽

Peitang Huang ◽

Xudong Zhu ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Transcription Factor ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Cell Line ◽

Hbv Infection ◽

Luciferase Reporter ◽

Artificial Transcription Factor ◽

Chronic Hepatitis B Virus ◽

B Virus

Chronic hepatitis B virus (HBV) infection is an independent risk factor for the development of hepatocellular carcinoma (HCC). The HBV HBx gene is frequently identified as an integrant in the chromosomal DNA of patients with HCC. HBx encodes the X protein (HBx), a putative viral oncoprotein that affects transcriptional regulation of several cellular genes. Therefore, HBx may be an ideal target to impede the progression of HBV infection–related HCC. In this study, integrated HBx was transcriptionally downregulated using an artificial transcription factor (ATF). Two three-fingered Cys2-His2 zinc finger (ZF) motifs that specifically recognized two 9-bp DNA sequences regulating HBx expression were identified from a phage-display library. The ZF domains were linked into a six-fingered protein that specified an 18-bp DNA target in the Enhancer I region upstream of HBx. This DNA-binding domain was fused with a Krüppel-associated box (KRAB) transcriptional repression domain to produce an ATF designed to downregulate HBx integrated into the Hep3B HCC cell line. The ATF significantly repressed HBx in a luciferase reporter assay. Stably expressing the ATF in Hep3B cells resulted in significant growth arrest, whereas stably expressing the ATF in an HCC cell line lacking integrated HBx (HepG2) had virtually no effect. The targeted downregulation of integrated HBx is a promising novel approach to inhibiting the progression of HBV infection–related HCC.

Download Full-text

Inverse biological coupling between the bone-specific transcription factor Runx2 and the tumor suppressor P53 levels in osteosarcoma

Bone ◽

10.1016/j.bone.2012.02.168 ◽

2012 ◽

Vol 50 ◽

pp. S61 ◽

Cited By ~ 2

Author(s):

H. Taipaleenmaki⁎ ◽

M. Van der Deen ◽

Y. Zhang ◽

J.B. Lian ◽

J.L. Stein ◽

...

Keyword(s):

Transcription Factor ◽

Tumor Suppressor ◽

Tumor Suppressor P53 ◽

Specific Transcription Factor ◽

Biological Coupling

Download Full-text

BRN2 is a non-canonical melanoma tumor-suppressor

Nature Communications ◽

10.1038/s41467-021-23973-5 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Michael Hamm ◽

Pierre Sohier ◽

Valérie Petit ◽

Jérémy H. Raymond ◽

Véronique Delmas ◽

...

Keyword(s):

Transcription Factor ◽

Transcription Factors ◽

Tumor Suppressor ◽

The Other ◽

Pi3k Signaling ◽

Melanoma Tumor ◽

Temporal Regulation ◽

Metastatic Colonization ◽

Pou Domain

AbstractWhile the major drivers of melanoma initiation, including activation of NRAS/BRAF and loss of PTEN or CDKN2A, have been identified, the role of key transcription factors that impose altered transcriptional states in response to deregulated signaling is not well understood. The POU domain transcription factor BRN2 is a key regulator of melanoma invasion, yet its role in melanoma initiation remains unknown. Here, in a BrafV600EPtenF/+ context, we show that BRN2 haplo-insufficiency promotes melanoma initiation and metastasis. However, metastatic colonization is less efficient in the absence of Brn2. Mechanistically, BRN2 directly induces PTEN expression and in consequence represses PI3K signaling. Moreover, MITF, a BRN2 target, represses PTEN transcription. Collectively, our results suggest that on a PTEN heterozygous background somatic deletion of one BRN2 allele and temporal regulation of the other allele elicits melanoma initiation and progression.

Download Full-text

Identification of the E1A-Regulated Transcription Factor p120E4F as an Interacting Partner of the RASSF1A Candidate Tumor Suppressor Gene

Cancer Research ◽

10.1158/0008-5472.can-03-2622 ◽

2004 ◽

Vol 64 (1) ◽

pp. 102-107 ◽

Cited By ~ 53

Author(s):

Sarah L. Fenton ◽

Ashraf Dallol ◽

Angelo Agathanggelou ◽

Luke Hesson ◽

Jalal Ahmed-Choudhury ◽

...

Keyword(s):

Transcription Factor ◽

Tumor Suppressor ◽

Tumor Suppressor Gene ◽

Suppressor Gene ◽

Candidate Tumor Suppressor ◽

Candidate Tumor Suppressor Gene

Download Full-text

Exploring the Role of a Novel Tumor Suppressor - OSR2 in T-ALL

Blood ◽

10.1182/blood-2020-142772 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 26-26

Author(s):

Arpan A. Sinha ◽

Pilar I. Andrade ◽

Megan Malone-Perez ◽

Syed T Ahmed ◽

J. Kimble Frazer

Keyword(s):

Transcription Factor ◽

Tumor Suppressor ◽

Childhood Cancer ◽

Conflicts Of Interest ◽

Lymphoblastic Leukemia ◽

Expression Patterns ◽

Tumor Biology ◽

Transgenic Animals ◽

Genetic Alterations ◽

Allelic Loss

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, representing >25% of all cancers in children 0-14 years. Despite major advancements in pediatric ALL treatment, it remains the second most lethal childhood cancer, accounting for ~25% of deaths. The two types of ALL are precursor-B, or B-ALL, and precursor-T, or T-ALL, which have distinct molecular landscapes. Of these types, T-ALL comprises about 15% and 25% of pediatric and adult cases, respectively, and is historically considered more aggressive and treatment-resistant, with an inferior prognosis. In the precision medicine era, it is imperative to identify genetic alterations and aberrant gene expression patterns, to better understand tumor biology and improve treatment outcomes by identifying new therapeutic targets. Our study investigates a novel transcription factor, odd-skipped related transcription factor 2 (OSR2), which we hypothesize is a putative T-ALL tumor suppressor. We are using a zebrafish T-ALL model expressing transgenic human MYC (hMYC) regulated by a lymphoblast-specific promoter, rag2. Prior work in zebrafish and human T-ALL found low OSR2 levels in ~95% of T-ALL. Based on this, we then used RNA-seq to analyze 10 hMYC zebrafish T-ALL, confirming low-to-absent osr2 in all 10 T-ALL relative to wild-type (WT) T cells. We further confirmed decreased osr2 expression by qRT-PCR of additional T-ALL and WT thymocytes. We hypothesized that if OSR2 suppresses T-ALL, impaired zebrafish Osr2 function might increase T-ALL incidence and shorten latency. To test this, we bred osr2-mutant fish to rag2:hMYC transgenic animals to create three genotypes: heterozygous osr2-mutant (osr2het) fish, heterozygous hMYC (hMYChet) fish, and compound-heterozygote (osr2het;hMYChet) fish. We screened these genotypes for T-ALL incidence by serial fluorescence microscopy, with T-ALL subsequently confirmed by fluorescence-based flow cytometry. By 7 months of age, we found 9/18 (50%) of double-heterozygous fish developed T-ALL, compared to 0/7 hMYChet fish (p = 0.026); osr2het fish also did not develop T-ALL. Together, our findings suggest osr2 allelic loss accelerates MYC-driven T-ALL, supporting our hypothesis that osr2 is a T-ALL tumor suppressor. Disclosures No relevant conflicts of interest to declare.

Download Full-text