A novel HMGA1-CCNE2-YAP axis regulates breast cancer aggressiveness.
High Mobility Group A1 (HMGA1) is an architectural chromatin factor that promotes neoplastic transformation and progression. However, the mechanism by which HMGA1 exerts its oncogenic function is not fully understood. Here, we show that cyclin E2 (CCNE2) acts downstream of HMGA1 to regulate the motility and invasiveness of basal-like breast cancer cells by promoting the nuclear localization and activity of YAP, the downstream mediator of the Hippo pathway. Mechanistically, the activity of MST1/2 and LATS1/2, the core kinases of the Hippo pathway, are required for the HMGA1- and CCNE2-mediated regulation of YAP localization. In breast cancer patients, high levels of HMGA1 and CCNE2 expression are associated with the YAP/TAZ signature, supporting this connection. Moreover, we provide evidence that CDK inhibitors induce the translocation of YAP from the nucleus to the cytoplasm, resulting in a decrease in its activity. These findings reveal an association between HMGA1 and the Hippo pathway that is relevant to stem cell biology, tissue homeostasis, and cancer.
Dipartimento di Scienze della Vita, Università degli Studi di Trieste, Trieste, Italy.
Silvia
S
Pegoraro
Dipartimento di Scienze della Vita, Università degli Studi di Trieste, Trieste, Italy.
Gloria
G
Ros
Dipartimento di Scienze della Vita, Università degli Studi di Trieste, Trieste, Italy.|Laboratorio Nazionale CIB (LNCIB), Area Science Park, Trieste, Italy.
Yari
Y
Ciani
Dipartimento di Scienze della Vita, Università degli Studi di Trieste, Trieste, Italy.
Riccardo
R
Sgarra
Laboratorio Nazionale CIB (LNCIB), Area Science Park, Trieste, Italy.
Silvano
S
Piazza
Dipartimento di Scienze della Vita, Università degli Studi di Trieste, Trieste, Italy.
Guidalberto
G
Manfioletti
D000217:Acyltransferases; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D016213:Cyclins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D057809:HEK293 Cells; D025741:HMGA1a Protein / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009361:Neoplasm Invasiveness; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
C503688:CCNE2 protein, human; D018797:Cell Cycle Proteins; D016213:Cyclins; D009687:Nuclear Proteins; D014157:Transcription Factors; C456659:YY1AP1 protein, human; D025741:HMGA1a Protein; D000217:Acyltransferases; C108675:TAFAZZIN protein, human
CDK inhibitors; Hippo pathway; YAP/TAZ; cyclin E2; oncogene/tumour suppressor