Dr Yuanyuan Zhang

Dr Yuanyuan Zhang

Research Associate

School of Biomedical Sciences and Pharmacy

Career Summary

Biography

Dr Yuanyuan Zhang has been working on cancer cell biology with a focused aim to understand the biological significance of long noncoding RNAs (lncRNAs) in cancer pathogenesis since the commencement of her PhD candidature in 2015. Her work has resulted in a co-first author publication about the lncRNA OVAAL in regulation of cancer cell apoptosis and senescence in the prestigious journal PNAS (PMID: 30478051), along with a first author paper published in Oncogene (PMID: 29706658). Yuanyuan Zhang obtained her PhD in Medicine from the University of Newcastle in 2019. Her past work not only enabled her to be trained systemically with techniques and skills necessary for lncRNA research, but also made her realise the complexity of the “lncRNA world”. As a logical extension, she continues investigating roles of lncRNAs in cancer development, progression and resistance to treatment.

Yuanyuan Zhang is currently a postdoctoral researcher at the University of Newcastle. She is employed through an NHMRC project grant held by Prof. Xu Dong Zhang. During this time, she contributes to strong training, supervision, and mentoring programs of Prof.  Zhang’s Lab. She is also assisting with supervision of RHD students and visiting academics.

Yuanyuan Zhang is a member of Institutional Biosafety Committee of the University of Newcastle. She is also an emergency warden at University.


Qualifications

  • Doctor of Philosophy, University of Newcastle

Keywords

  • Cell death
  • Long noncoding RNA
  • cancer

Fields of Research

Code Description Percentage
060103 Cell Development, Proliferation and Death 40
111201 Cancer Cell Biology 60

Professional Experience

UON Appointment

Title Organisation / Department
Research Associate University of Newcastle
School of Biomedical Sciences and Pharmacy
Australia

Awards

Member

Year Award
2018 Oral Presentation (Second Prize)
Australian Association of Chinese Biomedical Scientists
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Publications

For publications that are currently unpublished or in-press, details are shown in italics.


Journal article (13 outputs)

Year Citation Altmetrics Link
2018 Sang B, Zhang YY, Guo ST, Kong LF, Cheng Q, Liu GZ, et al., 'Dual functions for OVAAL in initiation of RAF/MEK/ERK prosurvival signals and evasion of p27-mediated cellular senescence', Proceedings of the National Academy of Sciences of the United States of America, 115 E11661-E11670 (2018) [C1]

© 2018 National Academy of Sciences. All Rights Reserved. Long noncoding RNAs (lncRNAs) function through a diverse array of mechanisms that are not presently fully understood. Her... [more]

© 2018 National Academy of Sciences. All Rights Reserved. Long noncoding RNAs (lncRNAs) function through a diverse array of mechanisms that are not presently fully understood. Here, we sought to find lncRNAs differentially regulated in cancer cells resistant to either TNF-related apoptosis-inducing ligand (TRAIL) or the Mcl-1 inhibitor UMI-77, agents that act through the extrinsic and intrinsic apoptotic pathways, respectively. This work identified a commonly up-regulated lncRNA, ovarian adenocarcinoma-amplified lncRNA (OVAAL), that conferred apoptotic resistance in multiple cancer types. Analysis of clinical samples revealed OVAAL expression was significantly increased in colorectal cancers and melanoma in comparison to the corresponding normal tissues. Functional investigations showed that OVAAL depletion significantly inhibited cancer cell proliferation and retarded tumor xenograft growth. Mechanically, OVAAL physically interacted with serine/threonine-protein kinase 3 (STK3), which, in turn, enhanced the binding between STK3 and Raf-1. The ternary complex OVAAL/STK3/Raf-1 enhanced the activation of the RAF protooncogene serine/threonine-protein kinase (RAF)/mito-gen-activated protein kinase kinase 1 (MEK)/ERK signaling cascade, thus promoting c-Myc¿mediated cell proliferation and Mcl-1¿mediated cell survival. On the other hand, depletion of OVAAL triggered cellular senescence through polypyrimidine tract-binding protein 1 (PTBP1)¿mediated p27 expression, which was regulated by competitive binding between OVAAL and p27 mRNA to PTBP1. Additionally, c-Myc was demonstrated to drive OVAAL transcription, indicating a positive feedback loop between c-Myc and OVAAL in controlling tumor growth. Taken together, these results reveal that OVAAL contributes to the survival of cancer cells through dual mechanisms controlling RAF/MEK/ERK signaling and p27-mediated cell senescence.

DOI 10.1073/pnas.1805950115
Citations Scopus - 2Web of Science - 4
Co-authors Rick Thorne, Xu Zhang, Lei Jin
2018 La T, Liu GZ, Farrelly M, Cole N, Feng YC, Zhang YY, et al., 'A p53-responsive miRNA network promotes cancer cell quiescence', Cancer Research, 78 6666-6679 (2018) [C1]

© 2018 American Association for Cancer Research. Cancer cells in quiescence (G0 phase) are resistant to death, and re-entry of quiescent cancer cells into the cell-cycle plays an ... [more]

© 2018 American Association for Cancer Research. Cancer cells in quiescence (G0 phase) are resistant to death, and re-entry of quiescent cancer cells into the cell-cycle plays an important role in cancer recurrence. Here we show that two p53-responsive miRNAs utilize distinct but complementary mechanisms to promote cancer cell quiescence by facilitating stabilization of p27. Purified quiescent B16 mouse melanoma cells expressed higher levels of miRNA-27b-3p and miRNA-455-3p relative to their proliferating counterparts. Induction of quiescence resulted in increased levels of these miRNAs in diverse types of human cancer cell lines. Inhibition of miRNA-27b-3p or miRNA-455-3p reduced, whereas its overexpression increased, the proportion of quiescent cells in the population, indicating that these miRNAs promote cancer cell quiescence. Accordingly, cancer xenografts bearing miRNA-27b-3p or miRNA-455-3p mimics were retarded in growth. miRNA-27b-3p targeted cyclin-dependent kinase regulatory subunit 1 (CKS1B), leading to reduction in p27 polyubiquitination mediated by S-phase kinase-associated protein 2 (Skp2). miRNA-455-3p targeted CDK2-associated cullin domain 1 (CAC1), which enhanced CDK2-mediated phosphorylation of p27 necessary for its polyubiquitination. Of note, the gene encoding miRNA-27b-3p was embedded in the intron of the chromosome 9 open reading frame 3 gene that was transcriptionally activated by p53. Similarly, the host gene of miRNA-455-3p, collagen alpha-1 (XXVII) chain, was also a p53 transcriptional target. Collectively, our results identify miRNA-27b-3p and miRNA-455-3p as important regulators of cancer cell quiescence in response to p53 and suggest that manipulating miRNA-27b-3p and miRNA-455-3p may constitute novel therapeutic avenues for improving outcomes of cancer treatment. Significance: Two novel p53-responsive microRNAs whose distinct mechanisms of action both stabilize p27 to promote cell quiescence and may serve as therapeutic avenues for improving outcomes of cancer treatment.

DOI 10.1158/0008-5472.CAN-18-1886
Co-authors Rick Thorne, Lei Jin, Xu Zhang
2018 Zhang YY, Tabataba H, Liu XY, Wang JY, Yan XG, Farrelly M, et al., 'ACTN4 regulates the stability of RIPK1 in melanoma', ONCOGENE, 37 4033-4045 (2018) [C1]
DOI 10.1038/s41388-018-0260-x
Citations Scopus - 3Web of Science - 3
Co-authors Rick Thorne, Xu Zhang, Lei Jin, Chenchen Jiang
2017 Liu F, Jiang CC, Yan XG, Tseng H-Y, Wang CY, Zhang YY, et al., 'BRAF/MEK inhibitors promote CD47 expression that is reversible by ERK inhibition in melanoma.', Oncotarget, 8 69477-69492 (2017) [C1]
DOI 10.18632/oncotarget.17704
Co-authors Chenchen Jiang
2017 Liu F, Jiang CC, Yan XG, Tseng H-Y, Wang CY, Zhang YY, et al., 'BRAF/MEK inhibitors promote CD47 expression that is reversible by ERK inhibition in melanoma.', Oncotarget, 8 69477-69492 (2017) [C1]
DOI 10.18632/oncotarget.17704
Citations Scopus - 4Web of Science - 4
Co-authors Xu Zhang, Rick Thorne, Chenchen Jiang, Lei Jin
2016 Yanwang C, Guo ST, Yuwang J, Liu F, Zhang YY, Yari H, et al., 'Inhibition of HSP90 by AUY922 preferentially kills mutantkrascolon cancer cellsbyactivatingbim through ER stress', Molecular Cancer Therapeutics, 15 448-459 (2016) [C1]

© 2016 American Association for Cancer Research. Oncogenic mutations of KRAS pose a great challenge in the treatment of colorectal cancer. Here we report that mutant KRAS colon ca... [more]

© 2016 American Association for Cancer Research. Oncogenic mutations of KRAS pose a great challenge in the treatment of colorectal cancer. Here we report that mutant KRAS colon cancer cells are nevertheless more susceptible to apoptosis induced by the HSP90 inhibitor AUY922 than those carrying wild-type KRAS. Although AUY922 inhibited HSP90 activity with comparable potency in colon cancer cells irrespective of their KRAS mutational statuses, those with mutant KRAS were markedly more sensitive to AUY922-induced apoptosis. This was associated with upregulation of the BH3-only proteins Bim, Bik, and PUMA.However, only Bim appeared essential, in that knockdown of Bim abolished, whereas knockdown of Bik or PUMA only moderately attenuated apoptosis induced by AUY922. Mechanistic investigations revealed that endoplasmic reticulum (ER) stress was responsible for AUY922-induced upregulation of Bim, which was inhibited by a chemical chaperone or overexpression of GRP78. Conversely, siRNA knockdown of GRP78 or XBP-1 enhanced AUY922-induced apoptosis. Remarkably, AUY922 inhibited the growth of mutant KRAS colon cancer xenografts through activation of Bim that was similarly associated with ER stress. Taken together, these results suggest that AUY922 is a promising drug in the treatment of mutant KRAS colon cancers, and the agents that enhance the apoptosis-inducing potential of Bimmaybe useful to improve the therapeutic efficacy.

DOI 10.1158/1535-7163.MCT-15-0778
Citations Scopus - 10Web of Science - 8
Co-authors Chenchen Jiang, Xu Zhang, Lei Jin
2016 Wang JY, Jin L, Yan XG, Sherwin S, Farrelly M, Zhang YY, et al., 'Reactive Oxygen Species Dictate the Apoptotic Response of Melanoma Cells to TH588', Journal of Investigative Dermatology, 136 2277-2286 (2016) [C1]

© 2016 The Authors The effect of MTH1 inhibition on cancer cell survival has been elusive. Here we report that although silencing of MTH1 does not affect survival of melanoma cell... [more]

© 2016 The Authors The effect of MTH1 inhibition on cancer cell survival has been elusive. Here we report that although silencing of MTH1 does not affect survival of melanoma cells, TH588, one of the first-in-class MTH1 inhibitors, kills melanoma cells through apoptosis independently of its inhibitory effect on MTH1. Induction of apoptosis by TH588 was not alleviated by MTH1 overexpression or introduction of the bacterial homolog of MTH1 that has 8-oxodGTPase activity but cannot be inhibited by TH588, indicating that MTH1 inhibition is not the cause of TH588-induced killing of melanoma cells. Although knockdown of MTH1 did not impinge on the viability of melanoma cells, it rendered melanoma cells sensitive to apoptosis induced by the oxidative stress inducer elesclomol. Of note, treatment with elesclomol also enhanced TH588-induced apoptosis, whereas a reactive oxygen species scavenger or an antioxidant attenuated the apoptosis triggered by TH588. Indeed, the sensitivity of melanoma cells to TH588 was correlated with endogenous levels of reactive oxygen species. Collectively, these results indicate that the cytotoxicity of TH588 toward melanoma cells is not associated with its inhibitory effect on MTH1, although it is mediated by cellular production of ROS.

DOI 10.1016/j.jid.2016.06.625
Citations Scopus - 14Web of Science - 11
Co-authors Lei Jin, Xu Zhang, Chenchen Jiang
2016 Wang CY, Guo ST, Wang JY, Yan XG, Farrelly M, Zhang YY, et al., 'Reactivation of ERK and Akt confers resistance of mutant BRAF colon cancer cells to the HSP90 inhibitor AUY922', Oncotarget, 7 49597-49610 (2016) [C1]

Oncogenic mutations of BRAF occur in approximately 10% of colon cancers and are associated with their resistance to clinically available therapeutic drugs and poor prognosis of th... [more]

Oncogenic mutations of BRAF occur in approximately 10% of colon cancers and are associated with their resistance to clinically available therapeutic drugs and poor prognosis of the patients. Here we report that colon cancer cells with mutant BRAF are also resistant to the heat shock protein 90 (HSP90) inhibitor AUY922, and that this is caused by rebound activation of ERK and Akt. Although AUY922 triggered rapid reduction in ERK and Akt activation in both wild-type and mutant BRAF colon cancer cells, activation of ERK and Akt rebounded shortly in the latter leading to resistance of the cells to AUY922-induced apoptosis. Reactivation of ERK was associated with the persistent expression of mutant BRAF, which, despite being a client of HSP90, was only partially degraded by AUY922, whereas reactivation of Akt was related to the activity of the HSP90 co-chaperone, cell division cycle 37 (CDC37), in that knockdown of CDC37 inhibited Akt reactivation in mutant colon cancer cells treated with AUY922. In support, as a HSP90 client protein, Akt was only diminished by AUY922 in wild-type but not mutant BRAF colon cancer cells. Collectively, these results reveal that reactivation of ERK and Akt associated respectively with the activity of mutant BRAF and CDC37 renders mutant BRAF colon cancer cells resistant to AUY922, with implications of co-targeting mutant BRAF and/or CDC37 and HSP90 in the treatment of mutant BRAF colon cancers.

DOI 10.18632/oncotarget.10414
Citations Scopus - 8Web of Science - 6
Co-authors Lei Jin, Chenchen Jiang, Xu Zhang
2014 Zhang Q, Zhang Y, Zhang P, Chao Z, Xia F, Jiang C, et al., 'Hexokinase II inhibitor, 3-BrPA induced autophagy by stimulating ROS formation in human breast cancer cells', Genes and Cancer, 5 100-112 (2014)

© 2014, Impact Journals LLC. All Rights Reserved. Hexokinase II (HKII), a key enzyme of glycolysis, is widely over-expressed in cancer cells. 3-bromopyruvate (3-BrPA), an inhibito... [more]

© 2014, Impact Journals LLC. All Rights Reserved. Hexokinase II (HKII), a key enzyme of glycolysis, is widely over-expressed in cancer cells. 3-bromopyruvate (3-BrPA), an inhibitor of HK II, has been proposed as a specific antitumor agent. Autophagy is a process that regulates the balance between protein synthesis and protein degradation. Autophagy in mammalian systems occurs under basal conditions and can be stimulated by stresses, including starvation, oxidative stress. Therefore, we hypothesized that 3-BrPA could induce autophagy. In the present study, we explored the mechanism of 3-BrPA and its combined action with chloroquine. Our results demonstrate that in MDA-MB-435 and in MDA-MB-231 cells, 3-BrPA induces autophagy, which can be inhibited by chloroquine. Furthermore, the combined treatment synergistically decreased the number of viable cells. Interestingly, the combined treatment triggered apoptosis in MDA-MB-435 cells, while it induced necroptosis in MDA-MB-231 cells. ROS mediated cell death when 3-BrPA and CQ were co-administered. Finally, CQ enhanced the anticancer efficacy of 3-BrPA in vivo. Collectively, our results show that 3-BrPA triggers autophagy, increasing breast cancer cell resistance to 3-BrPA treatment and that CQ enhanced 3-BrPA-induced cell death in breast cancer cells by stimulating ROS formation. Thus, inhibition of autophagy may be an innovative strategy for adjuvant chemotherapy of breast cancer

Citations Scopus - 31
Co-authors Chenchen Jiang, Xu Zhang
2014 Zhao RS, Zhang YY, Wu CZ, Li HM, Jiang C, Jiang ZW, Liu H, '3-bromopyruvate enhances cisplatin sensitivity of hepatocellular carcinoma cells in vitro.', Nan Fang Yi Ke Da Xue Xue Bao = Journal of Southern Medical University, 34 25-30 (2014) [C1]
Citations Scopus - 1
Co-authors Chenchen Jiang
2014 Liu Z, Zhang Y-Y, Zhang Q-W, Zhao S-R, Wu C-Z, Cheng X, et al., '3-Bromopyruvate induces apoptosis in breast cancer cells by downregulating Mcl-1 through the PI3K/Akt signaling pathway', ANTI-CANCER DRUGS, 25 447-455 (2014) [C1]
DOI 10.1097/CAD.0000000000000081
Citations Scopus - 22Web of Science - 22
Co-authors Chenchen Jiang
2014 Zhang P, Liu H, Xia F, Zhang QW, Zhang YY, Zhao Q, et al., 'Epithelial-mesenchymal transition is necessary for acquired resistance to cisplatin and increases the metastatic potential of nasopharyngeal carcinoma cells', INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE, 33 151-159 (2014) [C1]
DOI 10.3892/ijmm.2013.1538
Citations Scopus - 29Web of Science - 28
Co-authors Chenchen Jiang
2013 Zhang QW, Zhang YY, Zhao ZH, Zhang P, Jiang CC, Liu H, Jiang ZW, 'Influence of hydroxychloroquine on the proliferation and apoptosis of breast cancer cell MDA-MB-435', Chinese Pharmacological Bulletin, 29 1549-1553 (2013)

Aim: To observe the influence of hydroxychloroquine (HCQ) on the proliferation and apoptosis of breast cancer cell MDA-MB-435. Methods: The effect of HCQ on the proliferation of M... [more]

Aim: To observe the influence of hydroxychloroquine (HCQ) on the proliferation and apoptosis of breast cancer cell MDA-MB-435. Methods: The effect of HCQ on the proliferation of MDA-MB-435 cell was evaluated by MTT assay and clone formation assay; morphological changes of MDA-MB-435 cell after HCQ treatment was observed by inverted microscope; Hoechst 33258 staining was used to assess the changes in HCQ-induced apoptosis of MDA-MB-435 cell; PI staining was used to analyze the apoptosis of the cell exposed to HCQ; JC-1 was used to detect the changes of mitochondrial membrane potential of MDA-MB-435 cell. Results: Incubation with HCQ for 24 h, 48 h and 72 h resulted in a significant inhibition of MDA-MB-435 cell proliferation; HCQ treatment at different concentrations caused MDA-MB-435 cell turning round and shrinkage gradually, density of cell turning smaller gradually and losing the normal cell morphology; HCQ treatment also inhibited cell colony formation; Hoechst 33258 staining showed HCQ could induce apoptosis of MDA-MB-435 cell; exposure to 20, 40, 60 µmol · L -1 HCQ for 24 h caused a percentage of late apoptotic cells of 7.1%, 15.9%, 35.3% (P < 0.05); HCQ treatment at different concentrations also turned JC-1 from red to green (P < 0.05). Conclusion: HCQ can significantly inhibit the proliferation of MDA-MB-435 cell and induce apoptosis.

DOI 10.3969/j.issn.1001-1978.2013.11.018
Citations Scopus - 2
Co-authors Chenchen Jiang
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Conference (3 outputs)

Year Citation Altmetrics Link
2018 Tabatabaee H, Yari H, Feng Y, Zhang YY, La T, Lei J, Zhang XD, 'The Role of Ion Channels in Melanoma', ASIA-PACIFIC JOURNAL OF CLINICAL ONCOLOGY (2018)
Co-authors Xu Zhang
2018 Feng Y, Zhang XD, Jin L, Zhang YY, Yari H, La T, Tabatabaee H, 'Oncogenic upregulation of the long noncoding RNA5', ASIA-PACIFIC JOURNAL OF CLINICAL ONCOLOGY (2018)
Co-authors Lei Jin, Xu Zhang
2016 Wang CY, Guo ST, Wang JY, Yan XG, Farrelly M, Zhang YY, et al., 'REACTIVATION OF ERK AND AKT CONFERS RESISTANCE OF MUTANT BRAF COLON CANCER CELLS TO THE HSP90 INHIBITOR AUY922', ASIA-PACIFIC JOURNAL OF CLINICAL ONCOLOGY (2016)
Co-authors Xu Zhang, Lei Jin, Chenchen Jiang
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Research Projects

Dual functions for lncRNA OVAAL in initiation of RAF/MEK/ERK pro-survival signals and evasion of p27-mediated cellular senescence 2015 - 2018

In this project, I have identified that the c-Myc-regulating lncRNA OVAAL plays dual roles in both promoting cell proliferation and escaping apoptosis and senescence. Chromatin immunoprecipitation analyses confirmed that c-Myc bound the identified binding sites in the OVAAL promoter. On the one hand, OVAAL activates RAF/MEK/ERK cascade medicated prosurvival signalling through facilitating the binding between STK3 and Raf-1. The complex formed between OVAAL, STK3 and Raf-1 was confirmed using RNA pull down and two-step RNA immunoprecipitation assays. On the other hand, OVAAL blocks cellular senescence by regulating p27 mRNA translation through competing with p27 mRNA binding to the PTBP1 protein. OVAAL shRNA triggered cellular senescence was shown by induction of SA–β-gal staining. Deletion mapping analyses demonstrated RNA transcripts containing Exon 2 of OVAAL bound to the PTBP1 protein. (Proc Natl Acad Sci U S A. 2018 Dec 11;115(50):E11661-E11670.)


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Dr Yuanyuan Zhang

Position

Research Associate
School of Biomedical Sciences and Pharmacy
Faculty of Health and Medicine

Contact Details

Email yuanyuan.zhang@newcastle.edu.au
Phone (02) 49217827

Office

Room LS3-42
Building Life Science Building
Location Callaghan
University Drive
Callaghan, NSW 2308
Australia
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