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Featured researches published by Yanhong Zhang.


Oncogene | 2013

Histone deacetylase inhibitors suppress mutant p53 transcription via histone deacetylase 8

Wensheng Yan; Shou Liu; Enshun Xu; Jin Zhang; Yanhong Zhang; Xinbin Chen

Mutation of the p53 gene is the most common genetic alteration in human cancer and contributes to malignant process by enhancing transformed properties of cells and resistance to anticancer therapy. Mutant p53 is often highly expressed in tumor cells at least, in part, due to its increased half-life. However, whether mutant p53 expression is regulated by other mechanisms in tumors is unclear. Here we found that histone deacetylase (HDAC) inhibitors suppress both wild-type and mutant p53 transcription in time- and dose-dependent manners. Consistent with this, the levels of wild-type and mutant p53 proteins are decreased upon treatment with HDAC inhibitors. Importantly, we found that upon knockdown of each class I HDAC, only HDAC8 knockdown leads to decreased expression of wild-type and mutant p53 proteins and transcripts. Conversely, we found that ectopic expression of wild-type, but not mutant HDAC8, leads to increased transcription of p53. Furthermore, we found that knockdown of HDAC8 results in reduced expression of HoxA5 and consequently, attenuated ability of HoxA5 to activate p53 transcription, which can be rescued by ectopic expression of HoxA5. Because of the fact that HDAC8 is required for expression of both wild-type and mutant p53, we found that targeted disruption of HDAC8 expression remarkably triggers proliferative defect in cells with a mutant, but not wild-type, p53. Together, our data uncover a regulatory mechanism of mutant p53 transcription via HDAC8 and suggest that HDAC inhibitors and especially HDAC8-targeting agents might be explored as an adjuvant for tumors carrying a mutant p53.


Cancer Research | 2009

The G Protein–Coupled Receptor 87 Is Necessary for p53-Dependent Cell Survival in Response to Genotoxic Stress

Yanhong Zhang; Yingjuan Qian; Wenfu Lu; Xinbin Chen

p53 regulates an array of target genes, which mediates p53 tumor suppression by inducing cell cycle arrest, apoptosis, and cell survival. G protein-coupled receptors belong to a superfamily of cell surface molecules and are known to regulate cell proliferation, migration, and survival. Here, we found that G protein-coupled receptor 87 (GPR87) was up-regulated by p53 and by DNA damage in a p53-dependent manner. We also found that p53 directly regulated GPR87 potentially via a p53-responsive element in the GPR87 gene. To investigate the role of GPR87 in the p53 pathway, we generated multiple RKO and MCF7 cell lines in that GPR87 can be inducibly overexpressed or knocked down by a tetracycline-inducible system. We found that overexpression of GPR87 had little effect on cell growth. However, GPR87 knockdown sensitized cancer cells to DNA damage-induced growth suppression via enhanced p53 stabilization and activation. Importantly, the prosurvival activity of GPR87 can be reversed by knockdown of p53. Together, our results suggested that GPR87 is essential for p53-dependent cell survival in response to DNA damage. Thus, due to its expression on the cell surface and its role in cell survival, GPR87 may be explored as a novel therapeutic target for cancer treatment and prevention.


Journal of Cardiovascular Electrophysiology | 2016

Impact of Pulmonary Vein Cryoballoon Ablation on Bronchial Injury

Arash Aryana; Mark R. Bowers; Sa Man Hayatdavoudi; Yanhong Zhang; Alaa Afify; Andre d'Avila; Padraig Gearoid O'Neill

There is a paucity of data on the mechanisms of cough and hemoptysis that sometimes ensue from cryoballoon ablation of pulmonary veins (Cryo‐PV). This study specifically examined the impact of ultra‐cold (≤−60 °C, 3 minutes), prolonged (>−55 °C, 6 minutes), and conventional (>−55 °C, 3 minutes) Cryo‐PV on lung/bronchial injury.


PLOS ONE | 2013

PUMA Cooperates with p21 to Regulate Mammary Epithelial Morphogenesis and Epithelial-To-Mesenchymal Transition

Yanhong Zhang; Wensheng Yan; Yong Sam Jung; Xinbin Chen

Lumen formation is essential for mammary morphogenesis and requires proliferative suppression and apoptotic clearance of the inner cells within developing acini. Previously, we showed that knockdown of p53 or p73 leads to aberrant mammary acinus formation accompanied with decreased expression of p53 family targets PUMA and p21, suggesting that PUMA, an inducer of apoptosis, and p21, an inducer of cell cycle arrest, directly regulate mammary morphogenesis. To address this, we generated multiple MCF10A cell lines in which PUMA, p21, or both were stably knocked down. We found that morphogenesis of MCF10A cells was altered modestly by knockdown of either PUMA or p21 alone but markedly by knockdown of both PUMA and p21. Moreover, we found that knockdown of PUMA and p21 leads to loss of E-cadherin expression along with increased expression of epithelial-to-mesenchymal transition (EMT) markers. Interestingly, we found that knockdown of ΔNp73, which antagonizes the ability of wide-type p53 and TA isoform of p73 to regulate PUMA and p21, mitigates the abnormal morphogenesis and EMT induced by knockdown of PUMA or p21. Together, our data suggest that PUMA cooperates with p21 to regulate normal acinus formation and EMT.


Oncogene | 2014

P63 regulates tubular formation via epithelial-to-mesenchymal transition

Yanhong Zhang; Wensheng Yan; Xinbin Chen

P63, a p53 family member, is expressed as TA and ΔN isoforms. Interestingly, both TAp63 and ΔNp63 are transcription factors, and regulate both common and distinct sets of target genes. p63 is required for survival of some epithelial cell lineages, and lack of p63 leads to loss of epidermis and other epithelia in humans and mice. Here, we explored the role of p63 isoforms in cell proliferation, migration and tubulogenesis by using Madin–Darby Canine Kidney (MDCK) tubular epithelial cells in two- or three-dimensional (2-D or 3-D) culture. We found that like downregulation of p53, downregulation of p63 and TAp63 decreases expression of growth-suppressing genes, including p21, PUMA and MIC-1, and consequently promotes cell proliferation and migration in 2-D culture. However, in 3-D culture, downregulation of p63, especially TAp63, but not p53, decapacitates MDCK cells to form a cyst structure through enhanced epithelial-to-mesenchymal transition (EMT). In contrast, downregulation of ΔNp63 inhibits MDCK cell proliferation and migration in 2-D culture, and delays but does not block MDCK cell cyst formation and tubulogenesis in 3-D culture. Consistent with this, downregulation of ΔNp63 markedly upregulates growth-suppressing genes, including p21, PUMA and MIC-1. Taken together, these data suggest that TAp63 is the major isoform required for tubulogenesis by maintaining an appropriate level of EMT, whereas ΔNp63 fine-tunes the rate of cyst formation and tubulogenesis by maintaining an appropriate expression level of genes involved in cell cycle arrest and apoptosis.


PLOS ONE | 2013

Mutant p53 cooperates with knockdown of endogenous wild-type p53 to disrupt tubulogenesis in Madin-Darby canine kidney cells.

Yanhong Zhang; Wensheng Yan; Xinbin Chen

Mutation of the p53 gene is the most common genetic alteration in human malignances and associated clinically with tumor progression and metastasis. To determine the effect of mutant p53 on epithelial differentiation, we developed three-dimensional culture (3-D) of Madin-Darby canine kidney (MDCK) cells. We found that parental MDCK cells undergo a series of morphological changes and form polarized and growth-arrested cysts with hollow lumen, which resembles branching tubules in vitro. We also found that upon knockdown of endogenous wild-type p53 (p53-KD), MDCK cells still form normal cysts in 3-D culture, indicating that p53-KD alone is not sufficient to disrupt cysts formation. However, we found that ectopic expression of mutant R163H (human equivalent R175H) or R261H (human equivalent R273H) in MDCK cells leads to disruption of cyst polarity and formation of invasive aggregates, which is further compounded by knockdown of endogenous wild-type p53. Consistently, we found that expression of E-cadherin, β-catenin, and epithelial-to-mesenchymal transition (EMT) transcription factors (Snail-1, Slug and Twist) is altered by mutant p53, which is also compounded by knockdown of wild-type p53. Moreover, the expression level of c-Met, the hepatocyte growth factor receptor and a key regulator of kidney cell tubulogenesis, is enhanced by combined knockdown of endogenous wild-type p53 and ectopic expression of mutant R163H or R261H but not by each individually. Together, our data suggest that upon inactivating mutation of the p53 gene, mutant p53 acquires its gain of function by altering morphogenesis and promoting cell migration and invasion in part by upregulating EMT and c-Met.


PLOS ONE | 2014

Arsenic trioxide reactivates proteasome-dependent degradation of mutant p53 protein in cancer cells in part via enhanced expression of Pirh2 E3 ligase

Wensheng Yan; Yong Sam Jung; Yanhong Zhang; Xinbin Chen

The p53 gene is mutated in more than 50% of human tumors. Mutant p53 exerts an oncogenic function and is often highly expressed in cancer cells due to evasion of proteasome-dependent degradation. Thus, reactivating proteasome-dependent degradation of mutant p53 protein is an attractive strategy for cancer management. Previously, we found that arsenic trioxide (ATO), a drug for acute promyelocytic leukemia, degrades mutant p53 protein through a proteasome pathway. However, it remains unclear what is the E3 ligase that targets mutant p53 for degradation. In current study, we sought to identify an E3 ligase necessary for ATO-mediated degradation of mutant p53. We found that ATO induces expression of Pirh2 E3 ligase at the transcriptional level. We also found that knockdown of Pirh2 inhibits, whereas ectopic expression of Pirh2 enhances, ATO-induced degradation of mutant p53 protein. Furthermore, we found that Pirh2 E3 ligase physically interacts with and targets mutant p53 for polyubiquitination and subsequently proteasomal degradation. Interestingly, we found that ATO cooperates with HSP90 or HDAC inhibitor to promote mutant p53 degradation and growth suppression in tumor cells. Together, these data suggest that ATO promotes mutant p53 degradation in part via induction of the Pirh2-dependent proteasome pathway.


Genes & Development | 2017

Ferredoxin reductase is critical for p53-dependent tumor suppression via iron regulatory protein 2

Yanhong Zhang; Yingjuan Qian; Jin Zhang; Wensheng Yan; Yong Sam Jung; Mingyi Chen; Eric C. Huang; K. C. Kent Lloyd; Yuyou Duan; Jian Wang; Gang Liu; Xinbin Chen

Ferredoxin reductase (FDXR), a target of p53, modulates p53-dependent apoptosis and is necessary for steroidogenesis and biogenesis of iron-sulfur clusters. To determine the biological function of FDXR, we generated a Fdxr-deficient mouse model and found that loss of Fdxr led to embryonic lethality potentially due to iron overload in developing embryos. Interestingly, mice heterozygous in Fdxr had a short life span and were prone to spontaneous tumors and liver abnormalities, including steatosis, hepatitis, and hepatocellular carcinoma. We also found that FDXR was necessary for mitochondrial iron homeostasis and proper expression of several master regulators of iron metabolism, including iron regulatory protein 2 (IRP2). Surprisingly, we found that p53 mRNA translation was suppressed by FDXR deficiency via IRP2. Moreover, we found that the signal from FDXR to iron homeostasis and the p53 pathway was transduced by ferredoxin 2, a substrate of FDXR. Finally, we found that p53 played a role in iron homeostasis and was required for FDXR-mediated iron metabolism. Together, we conclude that FDXR and p53 are mutually regulated and that the FDXR-p53 loop is critical for tumor suppression via iron homeostasis.


CytoJournal | 2016

Pleural fluid metastases of myoepithelial carcinoma: A case report and review of the literature.

Alicia Calderon Bhambra; Yanhong Zhang; Eric C. Huang; John W. Bishop; Mahan Matin; Alaa Afify

Myoepithelial carcinoma (MECA) is one of the rarest salivary gland neoplasms, which may either arise de novo or develop within a preexisting pleomorphic adenoma or benign myoepithelioma. The tumor occurs mainly in the parotid gland followed by minor salivary glands and other body sites. As a result of their morphologic heterogeneity, they can be confused easily with many tumors. Awareness of their unique cytoarchitectural patterns and immunohistochemical profile is crucial for accurate identification. Herein, we report a rare case of a 51-year-old female patient with MECA of the maxillary sinus that metastasized to the pleural fluid. To the best of our knowledge, this is the first case of pleural fluid involvement by MECA reported in the literature.


Journal of Clinical Oncology | 2012

Raising the bar: Breast cancer biomarkers IHC4 harmonization from University of California-Athena pathology collaboration.

John W. Bishop; Jesse A. Engelberg; Sophia K. Apple; Ronald Balassanian; Alexander D. Borowsky; Robert D. Cardiff; Philip M. Carpenter; Yunn-Yi Chen; Brian Datnow; Sarah Elson; Farnaz Hasteh; Fritz Lin; Neda A. Moatamed; Brandon Perkovich; Yanhong Zhang

80 Background: Breast cancer treatment depends on the accurate analysis of immunohistochemical biomarkers (IHC4): estrogen and progesterone receptors, Ki-67, HER2. The Athena Harmonization project was undertaken to reduce technical and scoring variances between different laboratories and different pathologists. METHODS Initial assessment: Five breast cancer samples were sectioned and distributed to 5 UC campuses, where IHC4 and HER2 FISH tests were done per usual methods. Samples were selected to cover the range of negative, positive, and moderate for each antigen. Stained slides were circulated to 10 pathologists for scoring. Digital whole slide images (WSI) were made and scored. Technical variance reduction: A Delphi voting process identified an ideal histology slide for each IHC4 antigen. Laboratories adjusted techniques to match the appearance of the ideal slides, followed by pathologist and quantitative image analysis (QIA) validation. Scoring variance reduction: A digital pathology training tool was created where pathologists scored breast cancer tissue microarrays with known scores for the IHC4 antigens. RESULTS Scoring variance did not exceed clinical thresholds, although there were significant technical and scoring variances between laboratories that could affect research outcomes. The mean values and variance were similar for WSI and glass slides, except for HER2 (higher scores on WSI but without benefit of workstation calibration). Each laboratory adjusted technical parameters to more closely match the ideal IHC4. Early QIA data indicate reduced variance between adjusted and ideal histology slides. CONCLUSIONS Considerable and significant technical and interpretational variances between five University of California laboratories can be overcome by harmonizing protocols, setting new inter-institutional standards for pathology and histology best practices. Quantitative image analysis and whole slide imaging were instrumental. Subsequent harmonization will include cases near thresholds for clinical treatment guidelines.

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Xinbin Chen

University of California

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Wensheng Yan

University of California

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Alaa Afify

University of California

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Eric C. Huang

University of California

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John W. Bishop

University of California

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Yong Sam Jung

University of California

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Jin Zhang

University of California

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Yingjuan Qian

University of California

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