TY - JOUR
T1 - The co-chaperone UNC45A is essential for the expression of mitotic kinase NEK7 and tumorigenesis
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
AU - Maihle, Nita Jane
AU - Roig, Joan
AU - Korkaya, Hasan
AU - Cowell, John K.
AU - Chadli, Ahmed
N1 - Publisher Copyright:
© 2019 Eisa et al.
PY - 2019/4/5
Y1 - 2019/4/5
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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85064388090&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85064388090&partnerID=8YFLogxK
U2 - 10.1074/jbc.RA118.006597
DO - 10.1074/jbc.RA118.006597
M3 - Article
C2 - 30737284
AN - SCOPUS:85064388090
SN - 0021-9258
VL - 294
SP - 5246
EP - 5260
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 14
ER -