Selectively targeting BCL6 using a small molecule inhibitor is a potential therapeutic strategy for Glioblastoma

Abstract Glioblastoma (GBM) is the deadliest brain malignancy without effective treatments, and novel effective treatments are urgently needed. B cell lymphoma 6 (BCL6) is a transcription factor that stops cell death in response to DNA damage, primarily through repressing transcription of DNA damage response genes. Here, we identify BCL6 as a lynchpin in GBM, BCL6 expression was increased in GBM compared with normal cells and associated with GBM patients’ poor survival. Silencing of BCL6 additionally affected GBM cell proliferation and trigger cellular damage. Furthermore, we report the identification of WK499, a novel small-molecule inhibitor of BCL6. WK499 inhibited the growth of GBM cells by inhibiting BCL6 to activate p53-related signaling pathways, importantly, WK499 impeded significantly inhibition the growth of GBM cells both in vitro and in vivo. meanwhile, WK499 and TMZ Combination medication significantly suppresses tumor growth and metastasis in vivo and prolongs survival of tumor-bearing mice. In summary, our findings reveal a crucial role of BCL6 in GBM and suggest BCL6 as a therapeutic target for the treatment of this intractable disease.