Role of Tumor Suppressor Gene Products of Common Fragile Sites in Human Diseases
Common fragile sites (CFSs) are large chromosomal regions identified by conventional cytogenetics as sequences prone to breakage in cells subjected to replication stress. The interest in CFSs stems from their key role in DNA damage, resulting in chromosomal rearrangements. The instability of CFSs was correlated with genome instability in precancerous lesions and during tumor progression. Two opposing views dominate the discussion regarding the role of CFSs. One school of thought suggested that genomic instability during cancer progression causes collateral damage to genes residing within CFSs, such as WWOX and FHIT. These genes are proposed to be unselected ‘‘passenger’’ mutations. The counter argument is that deletions and other genomic alterations in CFSs occur early in cancer development. Cancer cells with deletions in genes that span CFSs are then selectively expanded due to loss of tumor suppressor functions such as protection of genome stability, coordination of cell cycle or apoptosis.
Recent observations from our lab clearly suggest that gene products of CFSs play driver roles in cancer transformation. Furthermore, accumulating evidence links some of these products with metabolic diseases and neuropathy. Investigating the role of these gene products in human diseases is a major interest of our lab work. The ultimate goal of our research is hence to discover the genes and to elucidate the pathways that represent targets for the development of rational, specific and effective therapeutic approaches.
Nareeman Abu Ghzaleh, Lab Manager
Rania Akkawi, Postdoc. student
Daniel Steinberg, MD-PhD student
Sara Oster, PhD student
Tirza Bidany, PhD student
Diala Shatleh, PhD student
Osama Hidmi, PhD student
Baraa Abu-Diab, PhD student
Kian Maroun, PhD student
Jingkai Wang, PhD student
Dania Abdellatif, PhD student
Lab Alumni
Yariv Cohen, MSc
Thesis Title: “Functional Association between WWOX and p73 and their involvement in the tumorigenic process”
Tomer Barmag, MSc
Thesis Title: “Characterizing new partners of the WWOX tumor suppressor protein”
Ortal Iancu, MSc
Thesis Title: “Functional cross-talk between WWOX and c-Fos in osteosarcoma development”
Sheeri Cohen, MSc
Thesis Title: “Regulation of Hippo signaling via WW domain interactions”
Keren Shemesh, MSc
Thesis Title: “Regulation of Hippo signaling via WW domain interactions”
Rand Arafeh, MSc
Thesis Title: “Role of microRNA 27a in osteosarcoma development”
Ella Abktekov, MSc
Thesis Title: “Role of the ubiquitin E3 ligase ITCH in breast carcinogenesis”
Dr. Zaidoun Salah, Post-doc
Currently Associate Professor at Al-Quds University
Dr. Vadim Maximov, Post-doc
Dr. Gili Bester, Lab Manager and Researcher
Sara Del Mare, PhD
Thesis Title: “WWOX as Signal mediator in Osteosarcoma development”
Mohammad Abu-Odeh, PhD
Thesis Title: “Role of WWOX fragile gene in DNA damage response”
Suhaib Abdeen, PhD
Thesis Title: “Role of Tumor Suppressor WWOX in Mammary Gland Development and Tumorigenicity”
Muhannad Abu-Remaileh, PhD
Thesis Title: “Tumor Suppressor WWOX as a Key Modulator of Cellular Metabolism”
Saleh Khawaled, PhD
Thesis Title: “Molecular and Cellular Role of Tumor Suppressor WWOX in Breast Cancer Metastasis”
Hazem Safadi, MSc
Thesis title: Feasibility of BLISS for Genome-Wide DNA Double Strand Breaks’ Profiling
Aya Shweiki, MSc
Thesis title: Functional interplay between tumour suppressors WWOX and BRCA1 in breast cancer development
Dr. Sri Repudi – post-doc
Project title: Modeling WOREE syndrome using GEMM
Houssan Hussieni, PhD
Thesis title: Role of WWOX in pancreatic carcinogenesis
Sara Abu-Swai, MSc
Thesis title: Role of WWOX in remyelination
Randa Tissawak, MSc
Thesis title: Role of WWOX in Ewing Sarcoma
Dr Lina Abu- Tair, Lab Manager and Post-doc researcher
Project Title: Role of tumor suppressor WWOX in carcinogenesis
Francis Mitri, MSc
Master thesis: Leveraging AAV for Precise and Targeted In Vivo Deletion of WWOX in Neurons
Selected Publications
Aqeilan RI, Trapasso F, Hussain S, Costinean S, Marshall D, Pekarsky Y, et al. Targeted deletion of Wwox reveals a tumor suppressor function. Proc Natl Acad Sci U S A 2007, 104(10): 3949-3954.
Aqeilan RI, Hassan MQ, de Bruin A, Hagan JP, Volinia S, Palumbo T, et al. The WWOX tumor suppressor is essential for postnatal survival and normal bone metabolism. J Biol Chem 2008, 283(31): 21629-21639.
Pichiorri F, Suh SS, Ladetto M, Kuehl M, Palumbo T, Drandi D, et al. MicroRNAs regulate critical genes associated with multiple myeloma pathogenesis. Proc Natl Acad Sci U S A 2008, 105(35): 12885-12890.
Aqeilan RI, Calin GA, Croce CM. miR-15a and miR-16-1 in cancer: discovery, function and future perspectives. Cell Death Differ 2010, 17(2): 215-220.
Kurek KC, Del Mare S, Salah Z, Abdeen S, Sadiq H, Lee SH, et al. Frequent attenuation of the WWOX tumor suppressor in osteosarcoma is associated with increased tumorigenicity and aberrant RUNX2 expression. Cancer Res 2010, 70(13): 5577-5586.
Pichiorri F, Suh SS, Rocci A, De Luca L, Taccioli C, Santhanam R, et al. Downregulation of p53-inducible microRNAs 192, 194, and 215 impairs the p53/MDM2 autoregulatory loop in multiple myeloma development. Cancer Cell 2010, 18(4): 367-381.
Abdeen SK, Salah Z, Maly B, Smith Y, Tufail R, Abu-Odeh M, et al. Wwox inactivation enhances mammary tumorigenesis. Oncogene 2011, 30(36): 3900-3906.
Del Mare S, Kurek KC, Stein GS, Lian JB, Aqeilan RI. Role of the WWOX tumor suppressor gene in bone homeostasis and the pathogenesis of osteosarcoma. Am J Cancer Res 2011, 1(5): 585-594.
Jones KB, Salah Z, Del Mare S, Galasso M, Gaudio E, Nuovo GJ, et al. miRNA signatures associate with pathogenesis and progression of osteosarcoma. Cancer Res 2012, 72(7): 1865-1877.
Abu-Odeh M, Bar-Mag T, Huang H, Kim T, Salah Z, Abdeen SK, et al. Characterizing WW domain interactions of tumor suppressor WWOX reveals its association with multiprotein networks. J Biol Chem 2014, 289(13): 8865-8880.
Abu-Odeh M, Salah Z, Herbel C, Hofmann TG, Aqeilan RI. WWOX, the common fragile site FRA16D gene product, regulates ATM activation and the DNA damage response. Proc Natl Acad Sci U S A 2014, 111(44): E4716-4725.
Abu-Remaileh M, Aqeilan RI. Tumor suppressor WWOX regulates glucose metabolism via HIF1alpha modulation. Cell Death Differ 2014, 21(11): 1805-1814.
Suh SS, Yoo JY, Cui R, Kaur B, Huebner K, Lee TK, et al. FHIT suppresses epithelial-mesenchymal transition (EMT) and metastasis in lung cancer through modulation of microRNAs. PLoS Genet 2014, 10(10): e1004652.
Abu-Remaileh M, Joy-Dodson E, Schueler-Furman O, Aqeilan RI. Pleiotropic Functions of Tumor Suppressor WWOX in Normal and Cancer Cells. J Biol Chem 2015, 290(52): 30728-30735.
Del Mare S, Husanie H, Iancu O, Abu-Odeh M, Evangelou K, Lovat F, et al. WWOX and p53 Dysregulation Synergize to Drive the Development of Osteosarcoma. Cancer Res 2016, 76(20): 6107-6117.
Hazan I, Hofmann TG, Aqeilan RI. Tumor Suppressor Genes within Common Fragile Sites Are Active Players in the DNA Damage Response. PLoS Genet 2016, 12(12): e1006436.
Abu-Remaileh M, Khalaileh A, Pikarsky E, Aqeilan RI. WWOX controls hepatic HIF1alpha to suppress hepatocyte proliferation and neoplasia. Cell Death Dis 2018, 9(5): 511.
Abu-Remaileh M, Abu-Remaileh M, Akkawi R, Knani I, Udi S, Pacold ME, Tam J, Aqeilan RI. WWOX somatic ablation in skeletal muscles alters glucose metabolism. Mol Metab. 2019 Apr;22:132-140.
Khawaled S, Suh SS, Abdeen SK, Monin J, Distefano R, Nigita G, Croce CM, Aqeilan RI. WWOX Inhibits Metastasis of Triple-Negative Breast Cancer Cells via
Modulation of miRNAs. Cancer Res. 2019 Apr 15;79(8):1784-1798.
Commentary by Sharma, P.: Quest for Tangible Biomarkers for Triple-Negative Breast Cancer. [Cancer Res. 2019]
Hazan I, Monin J, Bouwman BAM, Crosetto N, Aqeilan RI. Activation of Oncogenic Super-Enhancers Is Coupled with DNA Repair by RAD51. Cell Rep. 2019 Oct 15;29(3):560-572.e4.
Repudi S, Kustanovich I, Abu-Swai S, Stern S, Aqeilan RI. Neonatal neuronal WWOX gene therapy rescues Wwox null phenotypes. EMBO Mol Med. 2021 Dec 7;13(12):e14599.
The Lautenberg center for immunology and cancer research
Institute for Medical Research Israel-Canada (IMRIC), Faculty of Medicine, Hebrew University of Jerusalem
POB 12272, Jerusalem 91120, Israel
Tel: 972-2-6757725
Fax: 972-2-6430834
