BCL6 is regulated by the MAPK/ELK1 axis and promotes KRAS-driven lung cancer
Kun Li, … , Mingyao Liu, Xiufeng Pang
Kun Li, … , Mingyao Liu, Xiufeng Pang
Published November 15, 2022
Citation Information: J Clin Invest. 2022;132(22):e161308. https://doi.org/10.1172/JCI161308.
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Research Article Oncology

BCL6 is regulated by the MAPK/ELK1 axis and promotes KRAS-driven lung cancer

Abstract

Mutational activation of KRAS is a common oncogenic event in lung cancer, yet effective therapies are still lacking. Here, we identify B cell lymphoma 6 (BCL6) as a lynchpin in KRAS-driven lung cancer. BCL6 expression was increased upon KRAS activation in lung tumor tissue in mice and was positively correlated with the expression of KRAS-GTP, the active form of KRAS, in various human cancer cell lines. Moreover, BCL6 was highly expressed in human KRAS-mutant lung adenocarcinomas and was associated with poor patient survival. Mechanistically, the MAPK/ERK/ELK1 signaling axis downstream of mutant KRAS directly regulated BCL6 expression. BCL6 maintained the global expression of prereplication complex components; therefore, BCL6 inhibition induced stalling of the replication fork, leading to DNA damage and growth arrest in KRAS-mutant lung cancer cells. Importantly, BCL6-specific knockout in lungs significantly reduced the tumor burden and mortality in the LSL-KrasG12D/+ lung cancer mouse model. Likewise, pharmacological inhibition of BCL6 significantly impeded the growth of KRAS-mutant lung cancer cells both in vitro and in vivo. In summary, our findings reveal a crucial role of BCL6 in promoting KRAS-addicted lung cancer and suggest BCL6 as a therapeutic target for the treatment of this intractable disease.

Authors

Kun Li, Yanan Liu, Yi Ding, Zhengwei Zhang, Juanjuan Feng, Jiaxin Hu, Jiwei Chen, Zhengke Lian, Yiliang Chen, Kewen Hu, Zhi Chen, Zhenyu Cai, Mingyao Liu, Xiufeng Pang

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Figure 1

Mutant KRAS promotes BCL6 expression.

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Mutant KRAS promotes BCL6 expression. (A and B) mRNA (A) and protein (B)...
(A and B) mRNA (A) and protein (B) expression levels of BCL6 in normal lung (N) and tumor tissue (T) from LSL-KrasG12D/+ mice (n = 3). LSL-KrasG12D mice were infected with intranasal Ad-Cre for 16 weeks. (C and D) mRNA (C) and protein (D) expression levels of BCL6 in MEFs. MEFs were isolated from LSL-KrasG12D mice and infected with Ad-Cre for 72 hours (n = 3). (E) Correlation analysis. Correlation between BCL6 and KRAS-GTP protein expression levels in different cancer cell lines (n = 20). KRAS-GTP levels were determined using GST-RBD, the GST-fusion of the RAS binding domain of C-RAF, to pulldown active GTP-bound RAS from cellular lysates by glutathione beads. R, Pearson’s correlation coefficient. (F and G) KRAS mutant variants upregulated BCL6 expression at the mRNA (F) and protein (G) levels. 293T cells were transfected with different doxycycline-inducible G12 KRAS mutant variants: pLVX-TetOne-KRAS(G12C), pLVX-TetOne-KRAS(G12D), pLVX-TetOne-KRAS(G12S), pLVX-TetOne-KRAS(G12V). Transfected cells were then treated with or without 2 μM doxycycline (Dox) for 96 hours. KRAS activity was determined using GST-RAF-RBD to pulldown GTP-KRAS from cell lysates. (H) Heatmap showing differentially expressed BCL6 target genes (P < 0.05) in HPNE and HPNE/KRAS cells (n = 3). z score was calculated based on counts of exon model per million mapped reads. (I) The mRNA expression levels of BCL6 target gene in HPNE and HPNE/KRAS cells (n = 3). Data in A, C, F, and I are expressed as mean ± SEM of 3 technical replicates, representative of 3 independent experiments. *P < 0.05, **P < 0.01, ***P < 0.001, determined via unpaired 2-tailed Student’s t test. The immunoblots in B, D, and G were contemporaneous and run in parallel from the same biological replicate.