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Oncogenic dependency on STAT3 serine phosphorylation in KRAS mutant lung cancer

Oncogene volume 41, pages 809–823 (2022)Cite this article

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Abstract

The oncogenic potential of the latent transcription factor signal transducer and activator of transcription (STAT)3 in many human cancers, including lung cancer, has been largely attributed to its nuclear activity as a tyrosine-phosphorylated (pY705 site) transcription factor. By contrast, an alternate mitochondrial pool of serine phosphorylated (pS727 site) STAT3 has been shown to promote tumourigenesis by regulating metabolic processes, although this has been reported in only a restricted number of mutant RAS-addicted neoplasms. Therefore, the involvement of STAT3 serine phosphorylation in the pathogenesis of most cancer types, including mutant KRAS lung adenocarcinoma (LAC), is unknown. Here, we demonstrate that LAC is suppressed in oncogenic KrasG12D-driven mouse models engineered for pS727-STAT3 deficiency. The proliferative potential of the transformed KrasG12D lung epithelium, and mutant KRAS human LAC cells, was significantly reduced upon pS727-STAT3 deficiency. Notably, we uncover the multifaceted capacity of constitutive pS727-STAT3 to metabolically reprogramme LAC cells towards a hyper-proliferative state by regulating nuclear and mitochondrial (mt) gene transcription, the latter via the mtDNA transcription factor, TFAM. Collectively, our findings reveal an obligate requirement for the transcriptional activity of pS727-STAT3 in mutant KRAS-driven LAC with potential to guide future therapeutic targeting approaches.

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Fig. 1: Constitutive expression of serine phosphorylated STAT3 in human LAC patients and the KrasG12D LAC model.
Fig. 2: Suppressed KRAS-induced LAC in pS727-STAT3-deficient KrasG12D:Stat3SA/SA mice.
Fig. 3: pS727-STAT3 deficiency in the KrasG12D LAC mouse model and human LAC cells selectively suppresses cellular proliferation.
Fig. 4: pS727-STAT3 deficiency in human KRAS mutant LAC cells selectively suppresses cellular proliferation.
Fig. 5: pS727-STAT3-mediated dysregulation of oxidative stress and mitochondrial respiration in Kras mutant LAC associates with transcriptional regulation of nuclear- and mitochondrial-encoded genes.
Fig. 6: pS727-STAT3 binding to the promoter of Tfam and other STAT3-regulated genes modulates the transcription initiation activity of RNA Polymerase II.
Fig. 7: Heterozygous ablation of Stat3 suppresses KrasG12D-induced LAC.

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Acknowledgements

We are deeply grateful to D. Gough and S. Fernando (Hudson Institute of Medical Research, Melbourne, Australia) for expert technical assistance and proofreading of the manuscript, as well as A. Vais (Monash Histology Platform, Melbourne, Australia) for immunofluorescence expertise. This work was supported by a research grant awarded by the National Health and Medical Research Council (NHMRC) of Australia to BJJ, as well as the Operational Infrastructure Support Programme by the Victorian Government of Australia. MIS is supported by a Cancer Council Victoria Postdoctoral Fellowship. SA was sponsored by the Department of Chemistry, College of Sciences and Arts, King Abdulaziz University, Rabigh, Saudi Arabia. BJJ is supported by a NHMRC Senior Medical Research Fellowship.

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  1. These authors contributed equally: Sultan Alhayyani, Louise McLeod.

Authors and Affiliations

  1. Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, 3168, Australia

    Sultan Alhayyani, Louise McLeod, Alison C. West, Jesse J. Balic, Christopher Hodges, Liang Yu, Saleela M. Ruwanpura, Mohamed I. Saad & Brendan J. Jenkins

  2. Department of Molecular and Translational Science, School of Clinical Sciences, Monash University, Clayton, Victoria, 3168, Australia

    Sultan Alhayyani, Louise McLeod, Alison C. West, Jesse J. Balic, Christopher Hodges, Liang Yu, Saleela M. Ruwanpura, Mohamed I. Saad & Brendan J. Jenkins

  3. Department of Chemistry, College of Sciences and Arts, King Abdulaziz University, Rabigh, Saudi Arabia

    Sultan Alhayyani

  4. Department of Surgery, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, 3168, Australia

    Julian A. Smith

  5. Department of Cardiothoracic Surgery, Monash Health, Clayton, Victoria, 3168, Australia

    Julian A. Smith

  6. Monash Biobank, Monash Health, Clayton, Victoria, 3168, Australia

    Zdenka Prodanovic

  7. School of Health and Biomedical Sciences, RMIT University, Bundoora, Victoria, 3082, Australia

    Steven Bozinovski

  8. Department of Anatomical Pathology, Monash Health, Clayton, Victoria, 3168, Australia

    Beena Kumar

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Contributions

Conception and design: BJJ. Development of methodology: BJJ. Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): LM, SA, ACW, JJB, LY, JAS, ZP, SR, MIS, BJJ. Analysis and interpretation of data (e.g. statistical analysis, biostatistics, computational analysis): LM, SA, BK, SR, MIS, BJJ. Writing, review, and/or revision of the manuscript: BJJ. Administrative, technical, or material support (i.e. reporting or organising data, constructing databases): BJJ. Study supervision: SR, BJJ.

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Alhayyani, S., McLeod, L., West, A.C. et al. Oncogenic dependency on STAT3 serine phosphorylation in KRAS mutant lung cancer. Oncogene 41, 809–823 (2022). https://doi.org/10.1038/s41388-021-02134-4

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