Retinoblastoma protein as an intrinsic BRD4 inhibitor modulates small molecule BET inhibitor sensitivity in cancer

Donglin Ding, Rongbin Zheng, Ye Tian, Rafael Jimenez, Xiaonan Hou, Saravut J. Weroha, Liguo Wang, Lei Shi () and Haojie Huang ()
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Donglin Ding: Mayo Clinic College of Medicine and Science
Rongbin Zheng: Boston Children’s Hospital
Ye Tian: Affiliated Hospital of Nanjing University of Chinese Medicine
Rafael Jimenez: Mayo Clinic College of Medicine and Science
Xiaonan Hou: Mayo Clinic College of Medicine and Science
Saravut J. Weroha: Mayo Clinic College of Medicine and Science
Liguo Wang: Mayo Clinic College of Medicine and Science
Lei Shi: Mayo Clinic College of Medicine and Science
Haojie Huang: Mayo Clinic College of Medicine and Science

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract Bromodomain and extraterminal (BET) proteins including BRD4 play important roles in oncogenesis and immune inflammation. Here we demonstrate that cancer cells with loss of the retinoblastoma (RB) tumor suppressor became resistant to small molecule bromodomain inhibitors of BET proteins. We find that RB binds to bromodomain-1 (BD1) of BRD4, but binding is impeded by CDK4/6-mediated RB phosphorylation at serine-249/threonine-252 (S249/T252). ChIP-seq analysis shows RB knockdown increases BRD4 occupancy at genomic loci of genes enriched in cancer-related pathways including the GPCR-GNBIL-CREB axis. S249/T252-phosphorylated RB positively correlates with GNBIL protein level in prostate cancer patient samples. BET inhibitor resistance in RB-deficient cells is abolished by co-administration of CREB inhibitor. Our study identifies RB protein as a bona fide intrinsic inhibitor of BRD4 and demonstrates that RB inactivation confers resistance to small molecule BET inhibitors, thereby revealing a regulatory hub that converges RB upstream signaling onto BRD4 functions in diseases such as cancer.

Date: 2022
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DOI: 10.1038/s41467-022-34024-y

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