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Tania Moujaber Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney, New South Wales, Australia
Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
Crown Princess Mary Cancer Centre, Westmead Hospital, Western Sydney Local Health District, New South Wales, Australia
Blacktown Cancer and Haematology Centre, Blacktown Hospital, Western Sydney Local Health District, New South Wales, Australia

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Rosemary L Balleine Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney, New South Wales, Australia
Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
Children’s Medical Research Institute, Sydney, New South Wales, Australia

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Bo Gao Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney, New South Wales, Australia
Crown Princess Mary Cancer Centre, Westmead Hospital, Western Sydney Local Health District, New South Wales, Australia
Blacktown Cancer and Haematology Centre, Blacktown Hospital, Western Sydney Local Health District, New South Wales, Australia

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Ida Madsen Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney, New South Wales, Australia
Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
Department of Gynaecological Oncology, Westmead Hospital, Western Sydney Local Health District, New South Wales, Australia

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Paul R Harnett Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney, New South Wales, Australia
Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
Crown Princess Mary Cancer Centre, Westmead Hospital, Western Sydney Local Health District, New South Wales, Australia

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Anna DeFazio Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney, New South Wales, Australia
Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
Department of Gynaecological Oncology, Westmead Hospital, Western Sydney Local Health District, New South Wales, Australia
The Daffodil Centre, The University of Sydney, a joint venture with Cancer Council New South Wales, Sydney, New South Wales, Australia

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Low-grade serous ovarian cancer (LGSC) is a morphologically and molecularly distinct subtype of ovarian cancer, accounting for ~10% of serous carcinomas. Women typically present at a younger age and have a protracted clinical course compared with the more common, high-grade serous ovarian cancer. Currently, the primary treatment of LGSC is the same as other epithelial ovarian cancer subtypes, with treatment for most patients comprised of debulking surgery and platinum/taxane chemotherapy. Primary surgical cytoreduction to no visible residual disease remains a key prognostic factor; however, the use of platinum-based chemotherapy in both upfront and relapsed setting is being questioned due to low response rates in LGSC. Most LGSC expresses steroid hormone receptors, and selected patients may benefit from endocrine maintenance therapy following chemotherapy, in particular, those with evidence of residual disease at completion of surgery. In the recurrent setting, while hormonal therapies may offer disease stabilisation with relatively low toxicity, objective response rates remain low. Strategies to increase response rates, including combining with CDK4/6 inhibitors, are being investigated. LGSC has a high prevalence of activating somatic mutations in mitogen-activated protein kinase pathway genes, most commonly in KRAS, BRAF and NRAS. Trametinib, a MEK inhibitor, has shown efficacy over chemotherapy and endocrine therapy. The use of combination targeted therapies, immunotherapy and anti-angiogenic agents, remain active areas of investigation for the treatment of LGSC.

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Xi Wei Department of Diagnostic and Therapeutic Ultrasonography, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China

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Shang Cai Department of Oncology, Southern Research Institute and Cancer Cell Biology Program, the University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, Alabama, USA
Department of Radiotherapy and Oncology, the Second Affiliated Hospital of Soochow University, Suzhou, China

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Rebecca J Boohaker Department of Oncology, Southern Research Institute and Cancer Cell Biology Program, the University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, Alabama, USA

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Joshua Fried Department of Oncology, Southern Research Institute and Cancer Cell Biology Program, the University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, Alabama, USA

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Ying Li The Third Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China

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Linfei Hu Department of Thyroid Tumor, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China

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Yi Pan Department of Thyroid Tumor, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China

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Ruifen Cheng Department of Thyroid Tumor, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China

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Sheng Zhang Department of Diagnostic and Therapeutic Ultrasonography, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China

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Ye Tian Department of Radiotherapy and Oncology, the Second Affiliated Hospital of Soochow University, Suzhou, China

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Ming Gao Department of Thyroid Tumor, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China

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Bo Xu Department of Oncology, Southern Research Institute and Cancer Cell Biology Program, the University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, Alabama, USA
Department of Molecular Radiation Oncology, Key Laboratory of Breast Cancer Prevention and Therapy, Ministry of Education, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China

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Anaplastic thyroid cancer (ATC) is an aggressive cancer with poor clinical prognosis. However, mechanisms driving ATC aggressiveness is not well known. Components of the DNA damage response (DDR) are frequently found mutated or aberrantly expressed in ATC. The goal of this study is to establish the functional link between histone acetyltransferase lysine (K) acetyltransferase 5 (KAT5, a critical DDR protein) and ATC invasiveness using clinical, in vitro and in vivo models. We analyzed the expression of KAT5 by immunohistochemistry and assessed its relationship with metastasis and overall survival in 82 ATC patients. Using cellular models, we established functional connection of KAT5 expression and C-MYC stabilization. We then studied the impact of genetically modified KAT5 expression on ATC metastasis in nude mice. In clinical samples, there is a strong correlation of KAT5 expression with ATC metastasis (P = 0.0009) and overall survival (P = 0.0017). At the cellular level, upregulation of KAT5 significantly promotes thyroid cancer cell proliferation and invasion. We also find that KAT5 enhances the C-MYC protein level by inhibiting ubiquitin-mediated degradation. Further evidence reveals that KAT5 acetylates and stabilizes C-MYC. Finally, we prove that altered KAT5 expression influences ATC lung metastases in vivo. KAT5 promotes ATC invasion and metastases through stabilization of C-MYC, demonstrating it as a new biomarker and therapeutic target for ATC.

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