Journal Article

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

Tan, Hua, Wang, Guanwen, Cheng, Dongmei, Dong, George M., Su, Weijun, Sun, Peiqing, Wang, Juan, Wu, Dan, Ma, Ding A.

2022

Overview

Oncogene induced senescence is a tumor suppressing defense mechanism, in which the cell cycle-dependent protein kinase (CDK) inhibitor p16 INK4A (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 p16 INK4A gene. In the current study, we identified myeloid zinc finger 1 (MZF1) as the transcriptional factor that recruits CHD7 to the p16 INK4A promoter, where it mediates oncogenic ras -induced p16 INK4A 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 p16 INK4A levels. These findings have identified novel signaling components in the pathway that mediates induction of the p16 INK4A 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 p16 INK4A /RB pathway and disruption of senescence in tumor cells with intact RB.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/106 / 13/107 / 13/109 / 38/44 / 38/77 / 38/89 / 45/77 / 45/90 / 631/67/395 / 631/80/509 / 82/80 / 96/1 / Adenocarcinoma / Apoptosis / c-Jun protein / CDKN2A gene / Cell Biology / Cell cycle / Cell survival / DNA helicase / Enzyme inhibitors / Ets-1 protein / Extracellular signal-regulated kinase / Human Genetics / INK4a protein / Internal Medicine / Kinases / Lung cancer / Medicine / Medicine & Public Health / Non-small cell lung carcinoma / Oncogenes / Oncology / p16 Protein / Pancreatic cancer / Protein kinase / Raf protein / Senescence / Signal transduction / Small cell lung carcinoma / Transcription factors / Tumor cells / Tumor suppressor genes / Zinc finger proteins