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 Jacob Bollag, Nita Jane Maihle, Joan Roig, Hasan Korkaya, John Kenneth Cowell & 1 others Ahmed Chadli

Research output: Contribution to journalArticle

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
StatePublished - Jan 1 2019

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Myosins
Carcinogenesis
Phosphotransferases
Cell proliferation
Cells
Neoplasms
Cell Proliferation
Cell growth
Tumors
Genes
HSP90 Heat-Shock Proteins
Cytokinesis
Glucocorticoid Receptors
Gene Silencing
Metaphase
Microarrays
Chromosomes
Growth
NIMA-Related Kinases
Cell Nucleus

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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The co-chaperone UNC45A is essential for the expression of mitotic kinase NEK7 and tumorigenesis. / Eisa, Nada H.; Jilani, Yasmeen; Kainth, Kashish; Redd, Priscilla; Lu, Su; Bougrine, Oulia; Sater, Houssein Abdul; Patwardhan, Chaitanya A.; Shull, Austin; Shi, Huidong; Liu, Kebin; Elsherbiny, Nehal M.; Eissa, Laila A.; El-Shishtawy, Mamdouh M.; Horuzsko, Anatolij; Bollag, Roni Jacob; Maihle, Nita Jane; Roig, Joan; Korkaya, Hasan; Cowell, John Kenneth; Chadli, Ahmed.

In: Journal of Biological Chemistry, Vol. 294, No. 14, 01.01.2019, p. 5246-5260.

Research output: Contribution to journalArticle

Eisa, NH, Jilani, Y, Kainth, K, Redd, P, Lu, S, Bougrine, O, Sater, HA, Patwardhan, CA, Shull, A, Shi, H, Liu, K, Elsherbiny, NM, Eissa, LA, El-Shishtawy, MM, Horuzsko, A, Bollag, RJ, Maihle, NJ, Roig, J, Korkaya, H, Cowell, JK & Chadli, A 2019, 'The co-chaperone UNC45A is essential for the expression of mitotic kinase NEK7 and tumorigenesis', Journal of Biological Chemistry, vol. 294, no. 14, pp. 5246-5260. https://doi.org/10.1074/jbc.RA118.006597
Eisa, Nada H. ; Jilani, Yasmeen ; Kainth, Kashish ; Redd, Priscilla ; Lu, Su ; Bougrine, Oulia ; Sater, Houssein Abdul ; Patwardhan, Chaitanya A. ; Shull, Austin ; Shi, Huidong ; Liu, Kebin ; Elsherbiny, Nehal M. ; Eissa, Laila A. ; El-Shishtawy, Mamdouh M. ; Horuzsko, Anatolij ; Bollag, Roni Jacob ; Maihle, Nita Jane ; Roig, Joan ; Korkaya, Hasan ; Cowell, John Kenneth ; Chadli, Ahmed. / The co-chaperone UNC45A is essential for the expression of mitotic kinase NEK7 and tumorigenesis. In: Journal of Biological Chemistry. 2019 ; Vol. 294, No. 14. pp. 5246-5260.
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AU - Eisa, Nada H.

AU - Jilani, Yasmeen

AU - Kainth, Kashish

AU - Redd, Priscilla

AU - Lu, Su

AU - Bougrine, Oulia

AU - Sater, Houssein Abdul

AU - Patwardhan, Chaitanya A.

AU - Shull, Austin

AU - Shi, Huidong

AU - Liu, Kebin

AU - Elsherbiny, Nehal M.

AU - Eissa, Laila A.

AU - El-Shishtawy, Mamdouh M.

AU - Horuzsko, Anatolij

AU - Bollag, Roni Jacob

AU - Maihle, Nita Jane

AU - Roig, Joan

AU - Korkaya, Hasan

AU - Cowell, John Kenneth

AU - Chadli, Ahmed

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

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