TY - JOUR
T1 - SOX9 is essential for triple-negative breast cancer cell survival and metastasis
AU - Ma, Yanxia
AU - Shepherd, Jonathan
AU - Zhao, Dekuang
AU - Bollu, Lakshmi Reddy
AU - Tahaney, William M.
AU - Hill, Jamal
AU - Zhang, Yun
AU - Mazumdar, Abhijit
AU - Brown, Powel H.
N1 - Funding Information:
This work was supported by a NCI Cancer Center Support Grant (P30CA016672, to P.H. Brown), a Susan G. Komen Scientific Advisory Board Grant, SAB1600006 (to P.H. Brown), and a grant from the Breast Cancer Research Foundation 2015–2016 BCRF grant (to P.H. Brown), and by the John Charles Cain Endowment (to P.H. Brown). We would like to thank Michelle Savage for editing the manuscript, and Sam Short for assisting in the submission.
Funding Information:
Y. Ma reports grants from NCI Cancer Center Support Grant (P30CA016672, P.H. Brown), Susan G. Komen Scientific Advisory Board Grant (SAB1600006,
Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2020/12/1
Y1 - 2020/12/1
N2 - Triple-negative breast cancer (TNBC) has the worst prognosis of all breast cancers, and lacks effective targeted treatment strategies. Previously, we identified 33 transcription factors highly expressed in TNBC. Here, we focused on six sex determining region Y-related HMG-box (SOX) transcription factors (SOX4, 6, 8, 9, 10, and 11) highly expressed in TNBCs. Our siRNA screening assay demonstrated that SOX9 knockdown suppressed TNBC cell growth and invasion in vitro. Thus, we hypothesized that SOX9 is an important regulator of breast cancer survival and metastasis, and demonstrated that knockout of SOX9 reduced breast tumor growth and lung metastasis in vivo. In addition, we found that loss of SOX9 induced profound apoptosis, with only a slight impairment of G1 to S progression within the cell cycle, and that SOX9 directly regulates genes controlling apoptosis. On the basis of published CHIP-seq data, we demonstrated that SOX9 binds to the promoter of apoptosis-regulating genes (tnfrsf1b, fadd, tnfrsf10a, tnfrsf10b, and ripk1), and represses their expression. SOX9 knockdown upregulates these genes, consistent with the induction of apoptosis. Analysis of available CHIP-seq data showed that SOX9 binds to the promoters of several epithelial-mesenchymal transition (EMT)- and metastasis-regulating genes. Using CHIP assays, we demonstrated that SOX9 directly binds the promoters of genes involved in EMT (vim, cldn1, ctnnb1, and zeb1) and that SOX9 knockdown suppresses the expression of these genes. Implications: Our studies identified the SOX9 protein as a “master regulator” of breast cancer cell survival and metastasis, and provide preclinical rationale to develop SOX9 inhibitors for the treatment of women with metastatic triple-negative breast cancer.
AB - Triple-negative breast cancer (TNBC) has the worst prognosis of all breast cancers, and lacks effective targeted treatment strategies. Previously, we identified 33 transcription factors highly expressed in TNBC. Here, we focused on six sex determining region Y-related HMG-box (SOX) transcription factors (SOX4, 6, 8, 9, 10, and 11) highly expressed in TNBCs. Our siRNA screening assay demonstrated that SOX9 knockdown suppressed TNBC cell growth and invasion in vitro. Thus, we hypothesized that SOX9 is an important regulator of breast cancer survival and metastasis, and demonstrated that knockout of SOX9 reduced breast tumor growth and lung metastasis in vivo. In addition, we found that loss of SOX9 induced profound apoptosis, with only a slight impairment of G1 to S progression within the cell cycle, and that SOX9 directly regulates genes controlling apoptosis. On the basis of published CHIP-seq data, we demonstrated that SOX9 binds to the promoter of apoptosis-regulating genes (tnfrsf1b, fadd, tnfrsf10a, tnfrsf10b, and ripk1), and represses their expression. SOX9 knockdown upregulates these genes, consistent with the induction of apoptosis. Analysis of available CHIP-seq data showed that SOX9 binds to the promoters of several epithelial-mesenchymal transition (EMT)- and metastasis-regulating genes. Using CHIP assays, we demonstrated that SOX9 directly binds the promoters of genes involved in EMT (vim, cldn1, ctnnb1, and zeb1) and that SOX9 knockdown suppresses the expression of these genes. Implications: Our studies identified the SOX9 protein as a “master regulator” of breast cancer cell survival and metastasis, and provide preclinical rationale to develop SOX9 inhibitors for the treatment of women with metastatic triple-negative breast cancer.
UR - http://www.scopus.com/inward/record.url?scp=85100385209&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85100385209&partnerID=8YFLogxK
U2 - 10.1158/1541-7786.MCR-19-0311
DO - 10.1158/1541-7786.MCR-19-0311
M3 - Article
C2 - 32661114
AN - SCOPUS:85100385209
SN - 1541-7786
VL - 18
SP - 1825
EP - 1838
JO - Molecular Cancer Research
JF - Molecular Cancer Research
IS - 12
ER -