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MZF1 mediates oncogene-induced senescence by promoting the transcription of p16INK4A

Abstract

Oncogene induced senescence is a tumor suppressing defense mechanism, in which the cell cycle-dependent protein kinase (CDK) inhibitor p16INK4A (encoded by the CDKN2A gene) plays a key role. We previously reported that a transcriptional co-activator chromodomain helicase DNA binding protein 7 (CHD7) mediates oncogenic ras-induced senescence by inducing transcription of the p16INK4A gene. In the current study, we identified myeloid zinc finger 1 (MZF1) as the transcriptional factor that recruits CHD7 to the p16INK4A promoter, where it mediates oncogenic ras-induced p16INK4A transcription and senescence through CHD7, in primary human cells from multiple origins. Moreover, the expression of MZF1 is induced by oncogenic ras in senescent cells through the c-Jun and Ets1 transcriptional factors upon their activation by the Ras-Raf-1-MEK-ERK signaling pathway. In non-small cell lung cancer (NSCLC) and pancreatic adenocarcinoma (PAAD) where activating ras mutations occur frequently, reduced MZF1 expression is observed in tumors, as compared to corresponding normal tissues, and correlates with poor patient survival. Analysis of single cell RNA-sequencing data from PAAD patients revealed that among the tumor cells with normal RB expression levels, those with reduced levels of MZF1 are more likely to express lower p16INK4A levels. These findings have identified novel signaling components in the pathway that mediates induction of the p16INK4A tumor suppressor and the senescence response, and suggested that MZF1 is a potential tumor suppressor in at least some cancer types, the loss of which contributes to the inactivation of the p16INK4A/RB pathway and disruption of senescence in tumor cells with intact RB.

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Fig. 1: MZF1 mediates oncogenic ras-induced recruitment of CHD7 to the p16INK4A promoter and CHD7-stimulated p16INK4A transcription.
Fig. 2: The long MZF1 isoform mediates oncogenic ras-induced p16INK4A transcription.
Fig. 3: MZF1 mediates oncogenic ras-induced senescence through CHD7.
Fig. 4: Oncogenic ras induces MZF1 expression through the Raf1-MEK1-ERK pathway.
Fig. 5: Oncogenic ras-induced MZF1 transcription requires c-Jun and Ets1.
Fig. 6: The c-Jun and Ets1 binding sites on the MZF1 promoter are required for oncogenic ras-induced MZF1 transcription.
Fig. 7: Reduced MZF1 expression in tumors correlates with poor patient survival in NSCLC and PAAD.
Fig. 8: Analysis of single cell RNA-seq data reveals a correlation between low MZF1 expression and reduced CDKN2A/p16INK4A expression in PAAD.

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Acknowledgements

We thank the Cell Engineering and Cellular Imaging Shared Resources of WFBCCC. This study was supported by NIH/NCI grants CA131231, CA172115 and P30CA012197 (PS). PS is supported by the Anderson Oncology Research Professorship.

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DW, HT, WS and PS conceived and designed the study. DW, HT, WS, DC, GW, JW, DAM and GMD executed the experiments; DW, HT, WS, DAM, GMW and PS analyzed and interpreted the data. DW, HT and PS wrote and/or reviewed the manuscript.

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Correspondence to Peiqing Sun.

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Wu, D., Tan, H., Su, W. et al. MZF1 mediates oncogene-induced senescence by promoting the transcription of p16INK4A. Oncogene 41, 414–426 (2022). https://doi.org/10.1038/s41388-021-02110-y

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