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ASPM promotes prostate cancer stemness and progression by augmenting Wnt−Dvl-3−β-catenin signaling

Oncogene (2018) | Download Citation

Abstract

Recurrent and hormone-refractory prostate cancer (PCA) exhibits aggressive behaviors while current therapeutic approaches show little effect of prolonging the survival of patients with PCA. Thus, a deeper understanding of the patho-molecular mechanisms underlying the disease progression in PCA is crucial to identify novel diagnostic and/or therapeutic targets to improve the outcome of patients. Recent evidence suggests that activation of Wnt signaling in cancer stem cells (CSCs) contributes to cancer progression in malignant tumors. Here, we report that a novel Wnt co-activator ASPM (abnormal spindle-like microcephaly associated) maintains the prostate CSC subpopulation by augmenting the Wnt-β-catenin signaling in PCA. ASPM expression is incrementally upregulated in primary and metastatic PCA, implicating its potential role in PCA progression. Consistently, downregulation of ASPM expression pronouncedly attenuated the proliferation, colony formation, and the invasive behavior of PCA cells, and dramatically reduced the number of ALDH+ CSCs and inhibited cancer stemness and tumorigenicity. Mechanistically, ASPM interacts with disheveled-3 (Dvl-3), a cardinal upstream regulator of canonical Wnt signaling, and inhibits its proteasome-dependent degradation, thereby increasing its protein stability and enabling the Wnt-induced β-catenin transcriptional activity in PCA cells. In keeping with the role of ASPM as a CSC-regulator, ASPM co-localizes with ALDH in PCA tissues and its expression exhibits high intra-tumoral heterogeneity. The proportion of high-ASPM-expressing cells in the tumor inversely correlates with the relapse-free survival of PCA patients. Collectively, our data points to ASPM as a novel oncoprotein and an essential regulator of Wnt signaling and cancer stemness in PCA, which has important clinical and therapeutic significance.

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Acknowledgements

Supported in part by Ministry of Science and Technology grants MOST 104-2314-B-400-022, MOST 105-2314-B-400-018 (KKT), MOST 105-2314-B-400-003 (L-TC), Taipei Medical University grant DP2-107-21121-C-04 (KKT), Ministry of Health and Welfare grant MOHW107-TDU-B-212-114020 (KKT) and National Health Research Institutes intramural grant CA-106-PP-09 (KKT).

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Author notes

  1. These authors contributed equally: Vincent C. Pai, Chung-Chi Hsu.

Affiliations

  1. Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei City, 11031, Taiwan

    • Vincent C. Pai
    • , Chung-Chi Hsu
    • , Tze-Sian Chan
    •  & Kelvin K. Tsai
  2. Division of Gastroenterology, Department of Internal Medicine, Laboratory of Advanced Molecular Therapeutics, Wan Fang Hospital, Taipei Medical University, Taipei City, 11696, Taiwan

    • Chung-Chi Hsu
    • , Tze-Sian Chan
    •  & Kelvin K. Tsai
  3. National Institute of Cancer Research, National Health Research Institutes, Zhunan, Miaoli County, 35053, Taiwan

    • Vincent C. Pai
    • , Wen-Ying Liao
    • , Li-Tzong Chen
    •  & Kelvin K. Tsai
  4. Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Miaoli County, 35053, Taiwan

    • Chih-Pin Chuu
    •  & Ching-Yu Lin
  5. Department of Pathology, Wan Fang Hospital, Taipei Medical University, Taipei City, 11696, Taiwan

    • Wei-Yu Chen
  6. Department of Teaching and Research, Taichung Hospital, Ministry of Health and Welfare, Taichung City, 40343, Taiwan

    • Chi-Rong Li
  7. Department of Urology, Kaohsiung Medical University Chung-Ho Memorial Hospital, Kaohsiung City, 80756, Taiwan

    • Shu-Pin Hwang

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The authors declare that they have no conflict of interest.

Corresponding author

Correspondence to Kelvin K. Tsai.

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DOI

https://doi.org/10.1038/s41388-018-0497-4