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Cited by 37Protein Kinase Regulation and GTPase SignalingLung Cancer Treatments and MutationsLung Cancer Research Studies

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

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Li, Kun, Liu, Yanan, Ding, Yi, Zhang, Zhengwei, Feng, Juanjuan, Hu, Jiaxin, Chen, Jiwei, Lian, Zhengke +6 more·2022·Journal of Clinical Investigation
DOI 10.1172/jci161308PMC PMC9663163
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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.

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  • Upregulation of pioneer developmental organizers such as SOX2, KLF4, β-catenin, SNAIL-1, c-MYC, TBX3, and BCL6 is reported downstream of BRAF/MAPK-driven tumor.

    “Even upregulation of pioneer developmental organizers, such as SOX2, KLF4, β-catenin, SNAIL-1, c-MYC, TBX3, BCL6, et al., are reported downstream of BRAF/MAPK-driven tumor, the pathways causing lineage reprogramming are not clear12,15,30–36.”

    From Proteostatic reactivation of the developmental transcription factor TBX3 drives BRAF/MAPK-mediated tumorigenesis (2024) · cites this paper as [32]

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Cited by

Sorted by citations

Authors
Li, K., Liu, Y., Ding, Y., Zhang, Z., Feng, J., Hu, J., Chen, J., Lian, Z., Chen, Y., Hu, K., Chen, Z., Cai, Z., Liu, M., & Pang, X.
Affiliations
  • Shanghai Medical College of Fudan University (CN)
  • Shanghai Changning Maternity and Infant Health Hospital (CN)
  • Tongji University (CN)
  • Wuhan University (CN)
Corresponding author
Pang, Xiufeng
ORCID
Venue
Journal of Clinical Investigation
Publisher
American Society for Clinical Investigation
Published
2022-11-15
Volume
132
Issue
22
ISSN
  • 0021-9738 (ISSN-L)
  • 1558-8238
DOI
10.1172/jci161308
PMC
PMC9663163
OpenAlex
W4308992133
Cited by
37
References
10
Citations by year
2026: 5 · 2025: 11 · 2024: 17 · 2023: 4
FWCI
2.61
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Clinical Investigation (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • National Natural Science Foundation of China (82073073,82122045,81874207,81830083)
  • Innovative Research Team of High-level Local Universities in Shanghai (SHSMU-ZDCX20210802)
  • Jointed PI Program from Shanghai Changning Maternity and Infant Health Hospital (11300-412311-20033)
  • ECNU Construction Fund of Innovation and Entrepreneurship Laboratory (44400-20201-532300/021)
  • ECNU multifunctional platform for innovation (011)
  • MOE Key Laboratory of Biosystems Homeostasis & Protection (Zhejiang University)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
  • Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
Keywords
BCL6, KRAS mutation, lung cancer, lung adenocarcinoma, ERK signaling, Elk-1, pre-replication complex, replication fork stalling, DNA damage, tumor growth arrest, therapeutic target
MeSH terms
Adenocarcinoma of Lung, Animals, Disease Models, Animal, Humans, Lung Neoplasms, Mutation, Proto-Oncogene Proteins p21(ras), Cell Line, Tumor, ets-Domain Protein Elk-1, Mice, Proto-Oncogene Proteins c-bcl-6

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