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ALKATI interacts with c-Myc and promotes cancer stem cell-like properties in sarcoma

Oncogene volume 39, pages 151–163 (2020)Cite this article

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Abstract

Soft tissue sarcoma (STS) is a highly malignant tumor with limited targeted therapies. A novel anaplastic lymphoma kinase (ALK) transcript, ALKATI, was identified recently and could be targeted by ALK inhibitors in melanoma. However, the clinical and functional role of aberrant ALKATI expression in STS remains unknown. Here we demonstrate that as a new ALK transcript, ALKATI is frequently found in STS. ALKATI expression correlates with a lower probability of progression-free survival in STS patients. Compared with the other ALK isoforms, ALKATI expresses not only in the cytoplasm, but also in the nucleus of sarcoma cells. Functionally, overexpression of ALKATI promoted cancer stem cell (CSC)-like properties in sarcoma cells by promoting sphere formation and upregulating the expression of stem cell markers. Moreover, the ALK inhibitors not only suppressed the oncogenic functions of ALKATI but also attenuated ALKATI-induced CSC-like properties by reducing the expression of stem cell markers such as c-Myc, ABCG2, BMI1, and OCT4 both in vitro and in vivo. Furthermore, ALKATI interacted with c-Myc and increased the binding of c-Myc to the ABCG2 promoter, resulting in the induction of stem cell-like properties. Together, these findings indicate that ALKATI may be a potential prognostic marker and therapeutic target for STS patients harboring such ALK aberrations.

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Acknowledgements

This work was supported by the National Key Research and Development Program (2017YFA0505600) and the National Natural Science Foundation of China Programs (Grant Nos 81772863 and 81572403). We thank Dr Deng Xianming (Principal Investigator for Chemical Biology and Medicinal Chemistry School of Life Sciences, Xiamen University, China) for generously providing the plasmids.

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  1. These authors contributed equally: Bu-Shu Xu, Huo-Ying Chen

Authors and Affiliations

  1. Melanoma and Sarcoma Medical Oncology Unit, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, China

    Bu-Shu Xu, Huo-Ying Chen, Yi Que, Wei Xiao & Xing Zhang

  2. Department of Laboratory Medicine, The Second Affiliated Hospital of Guilin Medical University, Guilin, 541100, China

    Huo-Ying Chen

  3. State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, China

    Mu-Sheng Zeng

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Xu, BS., Chen, HY., Que, Y. et al. ALKATI interacts with c-Myc and promotes cancer stem cell-like properties in sarcoma. Oncogene 39, 151–163 (2020). https://doi.org/10.1038/s41388-019-0973-5

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