Zinc Finger Homeodomain Factor Zfhx3 Is Essential for Mammary Lactogenic Differentiation by Maintaining Prolactin Signaling Activity

Zhao, Dan; Ma, Guansheng; Zhang, Xiaolin; He, Yuan; Li, Mei; Han, Xueying; Fu, Liwei; Dong, Xue Yuan; Nagy, Tamás; Zhao, Qiang; Fu, Li; Dong, Jin Tang

doi:10.1074/jbc.m116.719377

Cited by 31 publications

(31 citation statements)

References 83 publications

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“…Clinical data for the patients were obtained from the open access cBioportal database [29,30]. Statistical analyses were carried out similar to a previous paper [31], briefly, two-tailed student’s t-test was used to assess statistical differences between two groups (for example, negative and positive ER, PR, HER2 status). One-way ANOVA followed by Bonferroni test was used to assess statistical differences for more than three groups.…”

Section: Methodsmentioning

confidence: 99%

Upregulation of Long Non-Coding RNA DRAIC Correlates with Adverse Features of Breast Cancer

Zhao

Dong

2018

ncRNA

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DRAIC (also known as LOC145837 and RP11-279F6.1), is a long non-coding RNA associated with several types of cancer including prostate cancer, lung cancer, and breast cancer. Its expression is elevated in tumor tissues compared to adjacent benign tissues in breast cancer patients and is regulated by estrogen treatment in breast cancer cells. In addition, expression analysis of DRAIC in more than 100 cell lines showed that DRAIC expression is high in luminal and basal subtypes compared to claudin low subtype, suggesting a prognostic value of DRAIC expression in breast cancer. In the present study, we analyzed DRAIC expression in 828 invasive breast carcinomas and 105 normal samples of RNA sequencing datasets from The Cancer Genome Atlas (TCGA) and found that DRAIC expression was correlated with estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status, and is increased in cancerous tissues. Additionally, higher DRAIC expression was associated with poorer survival of patients, especially in ER positive breast cancer. DRAIC was also investigated in the Oncomine database and we found that DRAIC expression predicted patients’ response to paclitaxel and FEC as well as lapatinib, which are commonly used therapy options for breast cancer. Finally, DRAIC expression in breast cancer was negatively correlated with immune cell infiltration. These results reinforce the importance of DRAIC in breast cancer.

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Section: Methodsmentioning

confidence: 99%

Upregulation of Long Non-Coding RNA DRAIC Correlates with Adverse Features of Breast Cancer

Zhao

Dong

2018

ncRNA

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“…ZFHX3 is rarely mutated in breast cancer (29), and ZFHX3 interacts with estrogen receptor alpha to modulate gene expression and cell proliferation in breast cancer cells (30,31). During postnatal development of mouse mammary glands, Zfhx3 is essential for the progesterone signaling to induce cell proliferation, side branching, and alveologenesis (32)(33)(34). ZFHX3 has also been implicated in other types of cancers including gastric, cervical, and head and neck (35).…”

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confidence: 99%

SUMOylation of the transcription factor ZFHX3 at Lys-2806 requires SAE1, UBC9, and PIAS2 and enhances its stability and function in cell proliferation

Fang

Liu

et al. 2020

Journal of Biological Chemistry

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SUMOylation is a posttranslational modification (PTM) at a lysine residue and is crucial for the proper functions of many proteins, particularly of transcription factors, in various biological processes. Zinc finger homeobox 3 (ZFHX3), also known as AT motif-binding factor 1 (ATBF1), is a large transcription factor that is active in multiple pathological processes, including atrial fibrillation and carcinogenesis, and in circadian regulation and development. We have previously demonstrated that ZFHX3 is SUMOylated at three or more lysine residues. Here, we investigated which enzymes regulate ZFHX3 SUMOylation and whether SUMOylation modulates ZFHX3 stability and function. We found that SUMO1, SUMO2, and SUMO3 each are conjugated to ZFHX3. Multiple lysine residues in ZFHX3 were SUMOylated, but Lys-2806 was the major SUMOylation site, and we also found that it is highly conserved among ZFHX3 orthologs from different animal species. Using molecular analyses, we identified the enzymes that mediate ZFHX3 SUMOylation; these included SUMO1-activating enzyme subunit 1 (SAE1), an E1-activating enzyme; SUMO-conjugating enzyme UBC9 (UBC9), an E2-conjugating enzyme; and protein inhibitor of activated STAT2 (PIAS2), an E3 ligase. Multiple analyses established that both SUMO-specific peptidase 1 (SENP1) and SENP2 deSUMOylate ZFHX3. SUMOylation at Lys-2806 enhanced ZFHX3 stability by interfering with its ubiquitination and proteasomal degradation. Functionally, Lys-2806 SUMOylation enabled ZFHX3-mediated cell proliferation and xenograft tumor growth of the MDA-MB-231 breast cancer cell line. These findings reveal the enzymes involved in, and the functional consequences of, ZFHX3 SUMOylation, insights that may help shed light on ZFHX3's roles in various cellular and pathophysiological processes.

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“…Moreover, the sublethality in heterozygous constitutive null mice suggests a haploinsufficiency in knockout mice. ZFHX3 plays vital roles in development and in other systems including mammary gland ( Zhao et al, 2016 ) and the nervous system ( Jung et al, 2005 ). Additionally, the transcription factor is known to play a role in tumorigenesis ( Cho et al, 2007 ; Sun et al, 2015 ) and has been consistently associated with atrial fibrillation ( Huang et al, 2015 ).…”

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Inducible Knockout of Mouse Zfhx3 Emphasizes Its Key Role in Setting the Pace and Amplitude of the Adult Circadian Clock

et al. 2017

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The transcription factor zinc finger homeobox 3 (ZFHX3) plays a key role in coupling intracellular transcriptional-translational oscillations with intercellular synchrony in mouse suprachiasmatic nucleus (SCN). However, like many key players in central nervous system function, ZFHX3 serves an important role in neurulation and neuronal terminal differentiation while retaining discrete additional functions in the adult SCN. Recently, using a dominant missense mutation in mouse Zfhx3, we established that this gene can modify circadian period and sleep in adult animals. Nevertheless, we were still concerned that the neurodevelopmental consequences of ZFHX3 dysfunction in this mutant may interfere with, or confound, its critical adult-specific roles in SCN circadian function. To circumvent the developmental consequences of Zfhx3 deletion, we crossed a conditional null Zfhx3 mutant to an inducible, ubiquitously expressed Cre line (B6.Cg-Tg(UBC-cre/ERT2)1Ejb/J). This enabled us to assess circadian behavior in the same adult animals both before and after Cre-mediated excision of the critical Zfhx3 exons using tamoxifen treatment. Remarkably, we found a strong and significant alteration in circadian behavior in tamoxifen-treated homozygous animals with no phenotypic changes in heterozygous or control animals. Cre-mediated excision of Zfhx3 critical exons in adult animals resulted in shortening of the period of wheel-running in constant darkness by more than 1 h in the majority of homozygotes while, in 30% of animals, excision resulted in complete behavioral arrhythmicity. In addition, we found that homozygous animals reentrain almost immediately to 6-h phase advances in the light-dark cycle. No additional overt phenotypic changes were evident in treated homozygous animals. These findings confirm a sustained and significant role for ZFHX3 in maintaining rhythmicity in the adult mammalian circadian system.

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Zinc Finger Homeodomain Factor Zfhx3 Is Essential for Mammary Lactogenic Differentiation by Maintaining Prolactin Signaling Activity

Cited by 31 publications

References 83 publications

Upregulation of Long Non-Coding RNA DRAIC Correlates with Adverse Features of Breast Cancer

Upregulation of Long Non-Coding RNA DRAIC Correlates with Adverse Features of Breast Cancer

SUMOylation of the transcription factor ZFHX3 at Lys-2806 requires SAE1, UBC9, and PIAS2 and enhances its stability and function in cell proliferation

Inducible Knockout of Mouse Zfhx3 Emphasizes Its Key Role in Setting the Pace and Amplitude of the Adult Circadian Clock

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