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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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 5

BCL6 inhibition results in replication fork stalling and DNA damage.

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BCL6 inhibition results in replication fork stalling and DNA damage. (A)...
(A) Gene set enrichment analysis of E2F targets in HPNE/KRAS (top) and MEF/KRAS cells (bottom). n = 3; NES, normalized enrichment score. (B) Heatmap showing E2F target gene expression in HPNE/KRAS and MEF/KRAS cells after BCL6 knockdown. z score was calculated based on counts of exon model per million mapped reads. n = 3. (C and D) Exogenous transduction of BCL6 (BCL6OV) restored expression of preRC genes in BCL6-depleted cells. H460 cells were transfected with BCL6 siRNAs alone or in combination with pcDNA 3.1-BCL6 vector. (E) MCM2 and MCM5 mRNA expression of sorted H460 cells. (F and G) DNA fiber analysis (n = 50 fibers). H460 cells were treated with genetic (F) or pharmacological approaches (10 μM COMP7) (G) Idu/CIdU ratio indicates red to green ratio. (H and I) Alkaline comet assays in H460 cells. The tail moment was defined as percentage of tail DNA × tail length using the Casp software. n = 30 cells. (J) BCL6 knockdown increased γ-H2AX expression. (K) BCL6 overexpression reduced MCM5 knockdown–mediated cytotoxicity. BCL6 and MCM5 expression (left) and the relative viability of cultured colonies (right) are shown. Data in C, E, F, G, H, I, and K were expressed as mean ± SEM Statistical analyses in C, E, F, H, and K were performed using 1-way ANOVA with Tukey’s multiple comparison test, and in G and I using unpaired 2-tailed Student’s t test, *P < 0.05, **P < 0.01, ***P < 0.001. The immunoblots in D, J, and K were contemporaneous and run in parallel from the same biological replicate, representative of at least 3 independent experiments.