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

A Correction to this article was published on 02 November 2018

This article has been updated

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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Change history

  • 02 November 2018

    In the published version of this paper the author Shu-Pin Huang’s surname was incorrectly given as Hwang instead of Huang. This has now been corrected in the HTML and PDF versions of the paper.

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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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Correspondence to Kelvin K. Tsai.

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Pai, V.C., Hsu, CC., Chan, TS. et al. ASPM promotes prostate cancer stemness and progression by augmenting Wnt−Dvl-3−β-catenin signaling. Oncogene 38, 1340–1353 (2019). https://doi.org/10.1038/s41388-018-0497-4

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