RAD21 promotes triple-negative breast cancer proliferation and metastasis via the repression of YAP-autophagy axis

Triple-negative breast cancer (TNBC), as the most aggressive subtype of breast cancer, has a poor prognosis because of its heterogeneity and complicated molecular mechanism. RAD21, a key component of cohesin complex, play vital roles in cellular functions and regulation of cell identity gene expression in cancer cells. However, it remains incompletely understood how RAD21 regulates tumorigenesis and metastasis in TNBC. Here, we present data suggesting that RAD21 was commonly highly expressed in TNBC and was correlated with poor outcome in invasive breast cancer. RAD21 depletion induced autophagy and suppress proliferation, invasion and xenograft tumor growth of TNBC cells, while RAD21 overexpression promoted lung metastasis. Mechanistically, RAD21 bound to the promoter region of the YAP and RAD21 knockdown increased YAP transcription level and the YAP nuclear accumulation in TNBC cells. Subsequently, YAP promoted a transcriptional program leading to enhanced autophagy flux to restrain TNBC cells proliferation and invasiveness. These findings uncover RAD21 as a promoter of TNBC tumorigenesis and metastasis and suggest a new function of RAD21 in regulating TNBC cells autophagy driven by YAP. RAD21 is linked to poor breast cancer outcomes. RAD21 is here found to drive TNBC tumor growth and invasion in vitro and in vivo by suppressing YAP transcription and YAP-mediated autophagy, revealing a novel YAP-dependent role.