Biology subjects

Teo, W. S.

Publications and source records attributed to Teo, W. S..

3 recordsLinked to original sources

bioRxiv2020

TIP60 acetylates H2AZ and regulates doxorubicin-induced DNA damage sensitivity through RAD51 transcription

TIP60, a lysine acetyltransferase and H2AZ, a histone H2A variant are involved in transcription and DNA repair. Recent studies suggest that H2AZ acetylation is dependent on TIP60. Here, we show that TIP60 acetylates both isoforms of H2AZ in vitro and in cells. Utilizing ChIP-seq and RNA-seq to identify the genes regulated by TIP60-dependent acetylation of H2AZ, we find that TIP60-dependent acetylation of H2AZ correlates with the expression of genes involved in DNA damage repair, amongst several other pathways. In line with this, TIP60-depleted cells exhibit increased sensitivity to the DNA damage-inducing drug doxorubicin. Restoring the expression level of RAD51, one of the genes involved in the DNA damage repair pathway, partially rescues the doxorubicin sensitivity due to TIP60 depletion. Overall, our study uncovers a role for TIP60 in regulating doxorubicin-induced DNA damage sensitivity in a manner dependent on RAD51 transcription.

molecular biology↗

bioRxiv2019

Targeting the Id1-Kif11-Aurka axis in triple negative breast cancer using combination therapy

Evidence points to breast cancer following a hierarchical model, with Cancer Stem Cells (CSCs) driving critical phenotypes of the bulk tumor. Chemoresistant CSCs are not an abstract concept but have clinical consequences as they drive relapse and ultimately lead to mortality in patients, making it imperative to understand how these subpopulations of cells survive. Our previous work (1-2) has demonstrated that the bHLH transcription factor, Inhibitor of Differentiation 1 (Id1) and its closely related family member Id3, have an important role in maintaining the CSC phenotype in the Triple Negative breast cancer (TNBC) subtype. A genetic screen conducted to further elucidate the molecular mechanism underlying the Id (Id1/3) mediated CSC phenotypes in TNBC revealed critical cell cycle genes such as Kif11 and Aurka as putative Id targets. We take this work forward by investigating how alteration in Kif11 and Aurka via Id proteins promotes the CSC phenotype in TNBC. Cells lacking Id are poised in a state of G0/G1 arrest from which they can re-enter the cell cycle. Intriguingly, depletion of Kif11 and Aurka independently did not phenocopy the G0/G1 arrest observed in Id knockdown (Id KD) cells. We have further explored the hypothesis that we can deplete the chemo resistant Id expressing CSC population by combining chemotherapy with targeted therapy using existing small molecule inhibitors (against Id target Kif11) to more effectively debulk the entire tumor. This work opens up exciting new possibilities of targeting Id targets like Kif11, in the TNBC subtype which is currently refractory to chemotherapy.

cancer biology↗

bioRxiv2018

Id proteins promote a cancer stem cell phenotype in triple negative breast cancer via Robo1-dependent c-Myc activation

Breast cancers display phenotypic and functional heterogeneity and several lines of evidence support the existence of cancer stem cells (CSCs) in certain breast cancers, a minor population of cells capable of tumor initiation and metastatic dissemination. Identifying factors that regulate the CSC phenotype is therefore important for developing strategies to treat metastatic disease. The Inhibitor of Differentiation Protein 1 (Id1) and its closely related family member Inhibitor of Differentiation 3 (Id3) (collectively termed Id) are expressed by a diversity of stem cells and are required for metastatic dissemination in experimental models of breast cancer. In this study, we show that ID1 is expressed in rare neoplastic cells within ER-negative breast cancers. To address the function of Id1 expressing cells within tumors, we developed two independent murine models of Triple Negative Breast Cancer (TNBC) in which a genetic reporter permitted the prospective isolation of Id1+ cells. Id1+ cells are enriched for self-renewal in tumorsphere assays in vitro and for tumor initiation in vivo. Conversely, depletion of Id1 and Id3 in the 4T1 murine model of TNBC demonstrates that Id1/3 are required for cell proliferation and self-renewal in vitro, as well as primary tumor growth and metastatic colonization of the lung in vivo. Using combined bioinformatic analysis, we have defined a novel mechanism of Id protein function via negative regulation of the Roundabout Axon Guidance Receptor Homolog 1 (Robo1) leading to activation of a Myc transcriptional programme.

cancer biology↗