Disrupting the interaction of BRD4 with diacetylated Twist suppresses tumorigenesis in basal-like breast cancer.
نویسندگان
چکیده
Twist is a key transcription activator of epithelial-mesenchymal transition (EMT). It remains unclear how Twist induces gene expression. Here we report a mechanism by which Twist recruits BRD4 to direct WNT5A expression in basal-like breast cancer (BLBC). Twist contains a "histone H4-mimic" GK-X-GK motif that is diacetylated by Tip60. The diacetylated Twist binds the second bromodomain of BRD4, whose first bromodomain interacts with acetylated H4, thereby constructing an activated Twist/BRD4/P-TEFb/RNA-Pol II complex at the WNT5A promoter and enhancer. Pharmacologic inhibition of the Twist-BRD4 association reduced WNT5A expression and suppressed invasion, cancer stem cell (CSC)-like properties, and tumorigenicity of BLBC cells. Our study indicates that the interaction with BRD4 is critical for the oncogenic function of Twist in BLBC.
منابع مشابه
Molecular and Cellular Pathobiology BRCA1 Suppresses Epithelial-to-Mesenchymal Transition and Stem Cell Dedifferentiation during Mammary and Tumor Development
BRCA1 mutation carriers are predisposed to developing basal-like breast cancers with high metastasis and poor prognosis. Yet, how BRCA1 suppresses formation of basal-like breast cancers is still obscure. Deletion of p18 (p18), an inhibitor of CDK4 and CDK6, functionally inactivates the RB pathway, stimulates mammary luminal stem cell (LSC) proliferation, and leads to spontaneous luminal tumor d...
متن کاملBRCA1 suppresses epithelial-to-mesenchymal transition and stem cell dedifferentiation during mammary and tumor development.
BRCA1 mutation carriers are predisposed to developing basal-like breast cancers with high metastasis and poor prognosis. Yet, how BRCA1 suppresses formation of basal-like breast cancers is still obscure. Deletion of p18(Ink4c) (p18), an inhibitor of CDK4 and CDK6, functionally inactivates the RB pathway, stimulates mammary luminal stem cell (LSC) proliferation, and leads to spontaneous luminal ...
متن کاملIs “Basal-like” Carcinoma of the Breast a Distinct Clinicopathologic Entity? A Critical Review with Cautionary Notes
This review deals with studies that have used cDNA microarrays and immunohistochemistry to identify a subtype of breast carcinoma recently known as “basal-like” carcinoma. The key breast carcinoma studies are critically discussed to highlight methodological problems in cohort selection, definitions, interpretation of results, an...
متن کاملHsa-miR-599 suppresses the migration and invasion by targeting BRD4 in breast cancer
Breast cancer is the second leading cause of cancer-associated mortality in females in the USA. Hsa-miR-599 was demonstrated to function as a tumour suppressor during cancer progression. However, the function and mechanism of the hsa-miR-599 in human breast cancer remain elusive. Thus, the aim of the present study was to investigate the potential role of hsa-miR-599 in breast cancer biology. Th...
متن کاملRole of endocrine disrupting chemicals on the tissue levels of AhR and sex steroid receptors in breast tumours
Breast cancer affects Iranian women at least one decade younger than their counterparts in othercountries and the incidence of breast fibroadenoma is growing in the last two decades in Tehran. Thisstudy aimed to compare the AhR levels in premenopausal breast cancer and breast fibroadnemo withappropriate normal groups. Possible associations of AhR with lifestyle and reproductive risk factorsand ...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید
ثبت ناماگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید
ورودعنوان ژورنال:
- Cancer cell
دوره 25 2 شماره
صفحات -
تاریخ انتشار 2014