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

Author:

Wu Min1,Zhang Lin1,Guo Weikai1,Lv Shiyi1,Jin Wangrui1,Zhu Shuangshuang1,Chen Huang2,Jian Shuyi1,Liu Layang1,Xing Yajing1,Liu Mingyao1ORCID,Chen Yihua1ORCID,Yi Zhengfang3ORCID

Affiliation:

1. East China Normal University

2. Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.

3. Institute of Biomedical Sciences and School of Life Sciences, East China Normal University

Abstract

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.

Publisher

Research Square Platform LLC

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