TY - JOUR
T1 - Hypoxia-induced suppression of alternative splicing of MBD2 promotes breast cancer metastasis via activation of FZD1
AU - Liu, Zhaoji
AU - Sun, Linchong
AU - Cai, Yongping
AU - Shen, Shengqi
AU - Zhang, Tong
AU - Wang, Nana
AU - Wu, Gongwei
AU - Ma, Wenhao
AU - Li, Shi Ting
AU - Suo, Caixia
AU - Hao, Yijie
AU - Jia, Wei Dong
AU - Semenza, Gregg L.
AU - Gao, Ping
AU - Zhang, Huafeng
N1 - Publisher Copyright:
©2020 American Association for Cancer Research.
PY - 2021/3/1
Y1 - 2021/3/1
N2 - Metastasis is responsible for the majority of breast cancer–related deaths, however, the mechanisms underlying metastasis in this disease remain largely elusive. Here we report that under hypoxic conditions, alternative splicing of MBD2 is suppressed, favoring the production of MBD2a, which facilitates breast cancer metastasis. Specifically, MBD2a promoted, whereas its lesser known short form MBD2c suppressed metastasis. Activation of HIF1 under hypoxia facilitated MBD2a production via repression of SRSF2-mediated alternative splicing. As a result, elevated MBD2a outcompeted MBD2c for binding to promoter CpG islands to activate expression of FZD1, thereby promoting epithelial-to-mesenchymal transition and metastasis. Strikingly, clinical data reveal significantly correlated expression of MBD2a and MBD2c with the invasiveness of malignancy, indicating opposing roles for MBD2 splicing variants in regulating human breast cancer metastasis. Collectively, our findings establish a novel link between MBD2 switching and tumor metastasis and provide a promising therapeutic strategy and predictive biomarkers for hypoxia-driven breast cancer metastasis. Significance: This study defines the opposing roles and clinical relevance of MBD2a and MBD2c, two MBD2 alternative splicing products, in hypoxia-driven breast cancer metastasis. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/81/5/1265/F1.large.jpg.
AB - Metastasis is responsible for the majority of breast cancer–related deaths, however, the mechanisms underlying metastasis in this disease remain largely elusive. Here we report that under hypoxic conditions, alternative splicing of MBD2 is suppressed, favoring the production of MBD2a, which facilitates breast cancer metastasis. Specifically, MBD2a promoted, whereas its lesser known short form MBD2c suppressed metastasis. Activation of HIF1 under hypoxia facilitated MBD2a production via repression of SRSF2-mediated alternative splicing. As a result, elevated MBD2a outcompeted MBD2c for binding to promoter CpG islands to activate expression of FZD1, thereby promoting epithelial-to-mesenchymal transition and metastasis. Strikingly, clinical data reveal significantly correlated expression of MBD2a and MBD2c with the invasiveness of malignancy, indicating opposing roles for MBD2 splicing variants in regulating human breast cancer metastasis. Collectively, our findings establish a novel link between MBD2 switching and tumor metastasis and provide a promising therapeutic strategy and predictive biomarkers for hypoxia-driven breast cancer metastasis. Significance: This study defines the opposing roles and clinical relevance of MBD2a and MBD2c, two MBD2 alternative splicing products, in hypoxia-driven breast cancer metastasis. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/81/5/1265/F1.large.jpg.
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U2 - 10.1158/0008-5472.CAN-20-2876
DO - 10.1158/0008-5472.CAN-20-2876
M3 - Article
C2 - 33402389
AN - SCOPUS:85102201038
SN - 0008-5472
VL - 81
SP - 1265
EP - 1278
JO - Cancer Research
JF - Cancer Research
IS - 5
ER -