The co-chaperone UNC45A is essential for the expression of mitotic kinase NEK7 and tumorigenesis

Nada H. Eisa, Yasmeen Jilani, Kashish Kainth, Priscilla Redd, Su Lu, Oulia Bougrine, Houssein Abdul Sater, Chaitanya A. Patwardhan, Austin Shull, Huidong Shi, Kebin Liu, Nehal M. Elsherbiny, Laila A. Eissa, Mamdouh M. El-Shishtawy, Anatolij Horuzsko, Roni Bollag, Nita Maihle, Joan Roig, Hasan Korkaya, John K. CowellAhmed Chadli

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

Cumulative evidence suggests that the heat shock protein 90 (Hsp90) co-chaperone UNC-45 myosin chaperone A (UNC45A) contributes to tumorigenesis and that its expression in cancer cells correlates with proliferation and metastasis of solid tumors. However, the molecular mechanism by which UNC45A regulates cancer cell proliferation remains largely unknown. Here, using siRNA-mediated gene silencing and various human cells, we report that UNC45A is essential for breast cancer cell growth, but is dispensable for normal cell proliferation. Immunofluorescence microscopy, along with gene microarray and RT-quantitative PCR analyses, revealed that UNC45A localizes to the cancer cell nucleus, where it up-regulates the transcriptional activity of the glucocorticoid receptor and thereby promotes expression of the mitotic kinase NIMA-related kinase 7 (NEK7). We observed that UNC45A-deficient cancer cells exhibit extensive pericentrosomal material disorganization, as well as defects in centrosomal separation and mitotic chromosome alignment. Consequently, these cells stalled in metaphase and cytokinesis and ultimately underwent mitotic catastrophe, phenotypes that were rescued by heterologous NEK7 expression. Our results identify a key role for the co-chaperone UNC45A in cell proliferation and provide insight into the regulatory mechanism. We propose that UNC45A represents a promising new therapeutic target to inhibit cancer cell growth in solid tumor types.

Original languageEnglish (US)
Pages (from-to)5246-5260
Number of pages15
JournalJournal of Biological Chemistry
Volume294
Issue number14
DOIs
Publication statusPublished - Jan 1 2019

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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