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 Therapeutics

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 4

BCL6 inhibition impedes the growth of KRAS-mutant cancer cells in vitro.

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BCL6 inhibition impedes the growth of KRAS-mutant cancer cells in vitro....
(A) Effects of BCL6 knockdown on cell survival. The knockdown efficiency of siBCL6 was examined (left) and cell viability was measured using a Cell Counting Kit-8 (CCK-8) (right). Relative cell viability (normalized to day 0) is plotted. (B) BCL6 depletion led to selective cytotoxic effects toward KRAS-mutant cancer cell lines. Thirteen KRAS-mutant and 7 KRAS-WT cancer cell lines were transfected with siBCL6 or a scrambled siRNA control. Cell viability was measured 72 hours after transfection using a CCK-8 assay kit. Relative cell viability is shown by setting the untreated control as 100%. (C) The colony-formation ability of indicated cell lines after transfection with siBCL6 or siControl. The relative clonogenic viability is calculated by normalizing the untreated group as 100%. (D) Exogenous transduction of BCL6 (BCL6OV) reduced BCL6 knockdown–mediated cytotoxicity. BCL6 expression (left) and the relative cell viability of cultured colonies (right) are shown. (E) The colony-formation ability of indicated cell lines after treatment with BCL6i. The relative viability of cultured colonies is calculated by normalizing the untreated group as 100%. (F) The inhibitory effects of COMP7 on HPNE and HPNE/KRAS cells. Cells were treated with COMP7 at gradient concentrations for 72 hours. (G) COMP 7 suppressed the clonogenic growth of various KRAS-mutant cancer cell lines. Cells were treated with 5 μM or 10 μM COMP7 for 7 days. Data in A, B, D, and F are expressed as mean ± SEM of 3 technical replicates. Statistical analyses in A, B, and D were performed using 1-way ANOVA with Tukey’s multiple comparison test, *P < 0.05, **P < 0.01, ***P < 0.001. The immunoblots in A and D were contemporaneous and run in parallel from the same biological replicate, representative of at least 3 independent experiments.