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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Gorgoulis V, Adams PD, Alimonti A, Bennett DC, Bischof O, Bishop C, et al. Cellular senescence: defining a path forward. Cell. 2019;179:813–27.
Krizhanovsky V, Xue W, Zender L, Yon M, Hernando E, Lowe SW. Implications of cellular senescence in tissue damage response, tumor suppression, and stem cell biology. Cold Spring Harb Symp Quant Biol. 2008;73:513–22.
Lee S, Lee JS. Cellular senescence: a promising strategy for cancer therapy. BMB Rep. 2019;52:35–41.
Lee S, Schmitt CA. The dynamic nature of senescence in cancer. Nat Cell Biol. 2019;21:94–101.
Zhu J, Woods D, McMahon M, Bishop JM. Senescence of human fibroblasts induced by oncogenic Raf. Genes Dev. 1998;12:2997–3007.
Ferbeyre G, de Stanchina E, Lin AW, Querido E, McCurrach ME, Hannon GJ, et al. Oncogenic ras and p53 cooperate to induce cellular senescence. Mol Cell Biol. 2002;22:3497–508.
Sato M, Vaughan MB, Girard L, Peyton M, Lee W, Shames DS, et al. Multiple oncogenic changes (K-RAS(V12), p53 knockdown, mutant EGFRs, p16 bypass, telomerase) are not sufficient to confer a full malignant phenotype on human bronchial epithelial cells. Cancer Res. 2006;66:2116–28.
Iwasaki O, Tanizawa H, Kim KD, Kossenkov A, Nacarelli T, Tashiro S, et al. Involvement of condensin in cellular senescence through gene regulation and compartmental reorganization. Nat Commun. 2019;10:5688.
Hernandez-Segura A, de Jong TV, Melov S, Guryev V, Campisi J, Demaria M. Unmasking transcriptional heterogeneity in senescent cells. Curr Biol. 2017;27:2652–2660 e2654.
Collado M, Serrano M. Senescence in tumours: evidence from mice and humans. Nat Rev Cancer. 2010;10:51–57.
di Magliano MP, Logsdon CD. Roles for KRAS in pancreatic tumor development and progression. Gastroenterology. 2013;144:1220–9.
Courtois-Cox S, Jones SL, Cichowski K. Many roads lead to oncogene-induced senescence. Oncogene. 2008;27:2801–9.
Hellmich C, Moore JA, Bowles KM, Rushworth SA. Bone marrow senescence and the microenvironment of hematological malignancies. Front Oncol. 2020;10:230.
Liu XL, Ding J, Meng LH. Oncogene-induced senescence: a double edged sword in cancer. Acta Pharm Sin. 2018;39:1553–8.
Ohtani N, Takahashi A, Mann DJ, Hara E. Cellular senescence: a double-edged sword in the fight against cancer. Exp Dermatol. 2012;21:1–4. Suppl 1
Schosserer M, Grillari J, Breitenbach M. The dual role of cellular senescence in developing tumors and their response to cancer therapy. Front Oncol. 2017;7:278.
Peterson MJ, Morris JF. Human myeloid zinc finger gene MZF produces multiple transcripts and encodes a SCAN box protein. Gene. 2000;254:105–18.
Murai K, Murakami H, Nagata S. A novel form of the myeloid-specific zinc finger protein (MZF-2). Genes Cells. 1997;2:581–91.
Eguchi T, Prince T, Wegiel B, Calderwood SK. Role and regulation of myeloid zinc finger protein 1 in cancer. J Cell Biochem. 2015;116:2146–54.
Brix DM, Bundgaard Clemmensen KK, Kallunki T. Zinc finger transcription factor MZF1-A specific regulator of cancer invasion. Cells. 2020;9:223.
Gaboli M, Kotsi PA, Gurrieri C, Cattoretti G, Ronchetti S, Cordon-Cardo C, et al. Mzf1 controls cell proliferation and tumorigenesis. Genes Dev. 2001;15:1625–30.
Hsieh YH, Wu TT, Tsai JH, Huang CY, Hsieh YS, Liu JY. PKCalpha expression regulated by Elk-1 and MZF-1 in human HCC cells. Biochem Biophys Res Commun. 2006;339:217–25.
Liu X, Lei Q, Yu Z, Xu G, Tang H, Wang W, et al. MiR-101 reverses the hypomethylation of the LMO3 promoter in glioma cells. Oncotarget. 2015;6:7930–43.
Tsai LH, Wu JY, Cheng YW, Chen CY, Sheu GT, Wu TC, et al. The MZF1/c-MYC axis mediates lung adenocarcinoma progression caused by wild-type lkb1 loss. Oncogene. 2015;34:1641–9.
Eguchi T, Prince TL, Tran MT, Sogawa C, Lang BJ. Calderwood SKMZF1 and SCAND1 reciprocally regulate CDC37 gene expression in prostate cancer. Cancers (Basel). 2019;11:792.
Hsieh YH, Wu TT, Huang CY, Hsieh YS, Liu JY. Suppression of tumorigenicity of human hepatocellular carcinoma cells by antisense oligonucleotide MZF-1. Chin J Physiol. 2007;50:9–15.
Rafn B, Nielsen CF, Andersen SH, Szyniarowski P, Corcelle-Termeau E, Valo E, et al. ErbB2-driven breast cancer cell invasion depends on a complex signaling network activating myeloid zinc finger-1-dependent cathepsin B expression. Mol Cell. 2012;45:764–76.
Tsai SJ, Hwang JM, Hsieh SC, Ying TH, Hsieh YH. Overexpression of myeloid zinc finger 1 suppresses matrix metalloproteinase-2 expression and reduces invasiveness of SiHa human cervical cancer cells. Biochem Biophys Res Commun. 2012;425:462–7.
Deng Y, Wang J, Wang G, Jin Y, Luo X, Xia X, et al. p55PIK transcriptionally activated by MZF1 promotes colorectal cancer cell proliferation. Biomed Res Int. 2013;2013:868131.
Lee JH, Kim SS, Lee HS, Hong S, Rajasekaran N, Wang LH, et al. Upregulation of SMAD4 by MZF1 inhibits migration of human gastric cancer cells. Int J Oncol. 2017;50:272–82.
Li GQ, He Q, Yang L, Wang SB, Yu DD, He YQ, et al. Clinical significance of myeloid zinc finger 1 expression in the progression of gastric tumourigenesis. Cell Physiol Biochem. 2017;44:1242–50.
Su W, Hong L, Xu X, Huang S, Herpai D, Li L, et al. miR-30 disrupts senescence and promotes cancer by targeting both p16(INK4A) and DNA damage pathways. Oncogene. 2018;37:5618–32.
Feng W, Shao C, Liu HK. Versatile roles of the chromatin remodeler CHD7 during brain development and disease. Front Mol Neurosci. 2017;10:309.
Feng W, Khan MA, Bellvis P, Zhu Z, Bernhardt O, Herold-Mende C, et al. The chromatin remodeler CHD7 regulates adult neurogenesis via activation of SoxC transcription factors. Cell Stem Cell. 2013;13:62–72.
Bajpai R, Chen DA, Rada-Iglesias A, Zhang J, Xiong Y, Helms J, et al. CHD7 cooperates with PBAF to control multipotent neural crest formation. Nature. 2010;463:958–62.
Schnetz MP, Handoko L, Akhtar-Zaidi B, Bartels CF, Pereira CF, Fisher AG, et al. CHD7 targets active gene enhancer elements to modulate ES cell-specific gene expression. PLoS Genet. 2010;6:e1001023.
Engelen E, Akinci U, Bryne JC, Hou J, Gontan C, Moen M, et al. Sox2 cooperates with Chd7 to regulate genes that are mutated in human syndromes. Nat Genet. 2011;43:607–11.
Roman M, Baraibar I, Lopez I, Nadal E, Rolfo C, Vicent S, et al. KRAS oncogene in non-small cell lung cancer: clinical perspectives on the treatment of an old target. Mol Cancer. 2018;17:33.
Waters AM, Der CJ. KRAS: the critical driver and therapeutic target for pancreatic cancer. Cold Spring Harb Perspect Med. 2018;8:a031435.
Schnetz MP, Bartels CF, Shastri K, Balasubramanian D, Zentner GE, Balaji R, et al. Genomic distribution of CHD7 on chromatin tracks H3K4 methylation patterns. Genome Res. 2009;19:590–601.
Sun L, Yu R, Dang W. Chromatin architectural changes during cellular senescence and aging. Genes. 2018;9:211.
Yokoyama Y, Zhu H, Zhang R, Noma K. A novel role for the condensin II complex in cellular senescence. Cell Cycle 2015;14:2160–70.
Ulianov SV, Khrameeva EE, Gavrilov AA, Flyamer IM, Kos P, Mikhaleva EA, et al. Active chromatin and transcription play a key role in chromosome partitioning into topologically associating domains. Genome Res. 2016;26:70–84.
Yokoyama Y, Zhu H, Zhang R, Noma K. A novel role for the condensin II complex in cellular senescence. Cell Cycle. 2015;14:2160–70.
Li W, Hu Y, Oh S, Ma Q, Merkurjev D, Song X, et al. Condensin I and II complexes license full estrogen receptor alpha-dependent enhancer activation. Mol Cell. 2015;59:188–202.
Kagey MH, Newman JJ, Bilodeau S, Zhan Y, Orlando DA, van Berkum NL, et al. Mediator and cohesin connect gene expression and chromatin architecture. Nature. 2010;467:430–5.
Kwong J, Chen M, Lv D, Luo N, Su W, Xiang R, et al. Induction of p38delta expression plays an essential role in oncogenic ras-induced senescence. Mol Cell Biol. 2013;33:3780–94.
Kanojia D, Panek WK, Cordero A, Fares J, Xiao A, Savchuk S, et al. BET inhibition increases betaIII-tubulin expression and sensitizes metastatic breast cancer in the brain to vinorelbine. Sci Transl Med. 2020;12:eaax2879.
Gyorffy B, Lanczky A, Eklund AC, Denkert C, Budczies J, Li Q, et al. An online survival analysis tool to rapidly assess the effect of 22,277 genes on breast cancer prognosis using microarray data of 1,809 patients. Breast Cancer Res Treat. 2010;123:725–31.
Romagosa C, Simonetti S, Lopez-Vicente L, Mazo A, Lleonart ME, Castellvi J, et al. p16(Ink4a) overexpression in cancer: a tumor suppressor gene associated with senescence and high-grade tumors. Oncogene. 2011;30:2087–97.
Schwartz B, Avivi-Green C, Polak-Charcon S. Sodium butyrate induces retinoblastoma protein dephosphorylation, p16 expression and growth arrest of colon cancer cells. Mol Cell Biochem. 1998;188:21–30.
Herschkowitz JI, He X, Fan C, Perou CM. The functional loss of the retinoblastoma tumour suppressor is a common event in basal-like and luminal B breast carcinomas. Breast Cancer Res. 2008;10:R75.
Dublin EA, Patel NK, Gillett CE, Smith P, Peters G, Barnes DM. Retinoblastoma and p16 proteins in mammary carcinoma: their relationship to cyclin D1 and histopathological parameters. Int J Cancer. 1998;79:71–75.
Gorgoulis VG, Zacharatos P, Kotsinas A, Liloglou T, Kyroudi A, Veslemes M, et al. Alterations of the p16-pRb pathway and the chromosome locus 9p21-22 in non-small-cell lung carcinomas: relationship with p53 and MDM2 protein expression. Am J Pathol. 1998;153:1749–65.
Bastide K, Guilly MN, Bernaudin JF, Joubert C, Lectard B, Levalois C, et al. Molecular analysis of the Ink4a/Rb1-Arf/Tp53 pathways in radon-induced rat lung tumors. Lung Cancer. 2009;63:348–53.
Peng J, Sun BF, Chen CY, Zhou JY, Chen YS, Chen H, et al. Single-cell RNA-seq highlights intra-tumoral heterogeneity and malignant progression in pancreatic ductal adenocarcinoma. Cell Res. 2019;29:725–38.
Chen Y, Zhang Z, Yang K, Du J, Xu Y, Liu S. Myeloid zinc-finger 1 (MZF-1) suppresses prostate tumor growth through enforcing ferroportin-conducted iron egress. Oncogene. 2015;34:3839–47.
Tvingsholm SA, Hansen MB, Clemmensen KKB, Brix DM, Rafn B, Frankel LB, et al. Let-7 microRNA controls invasion-promoting lysosomal changes via the oncogenic transcription factor myeloid zinc finger-1. Oncogenesis. 2018;7:14.
LaPak KM, Burd CE. The molecular balancing act of p16(INK4a) in cancer and aging. Mol Cancer Res. 2014;12:167–83.
Coppe JP, Rodier F, Patil CK, Freund A, Desprez PY, Campisi J. Tumor suppressor and aging biomarker p16(INK4a) induces cellular senescence without the associated inflammatory secretory phenotype. J Biol Chem. 2011;286:36396–403.
Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell. 1997;88:593–602.
Kotake Y, Naemura M, Murasaki C, Inoue Y, Okamoto H. Transcriptional regulation of the p16 tumor suppressor gene. Anticancer Res. 2015;35:4397–401.
Brookes S, Rowe J, Ruas M, Llanos S, Clark PA, Lomax M, et al. INK4a-deficient human diploid fibroblasts are resistant to RAS-induced senescence. EMBO J. 2002;21:2936–45.
Braig M, Lee S, Loddenkemper C, Rudolph C, Peters AH, Schlegelberger B, et al. Oncogene-induced senescence as an initial barrier in lymphoma development. Nature. 2005;436:660–5.
Zhang Y, Tong T. FOXA1 antagonizes EZH2-mediated CDKN2A repression in carcinogenesis. Biochem Biophys Res Commun. 2014;453:172–8.
Ouyang XS, Wang X, Ling MT, Wong HL, Tsao SW, Wong YC. Id-1 stimulates serum independent prostate cancer cell proliferation through inactivation of p16(INK4a)/pRB pathway. Carcinogenesis. 2002;23:721–5.
Vishwamitra D, Curry CV, Alkan S, Song YH, Gallick GE, Kaseb AO, et al. The transcription factors Ik-1 and MZF1 downregulate IGF-IR expression in NPM-ALK(+) T-cell lymphoma. Mol Cancer. 2015;14:53.
Zhang S, Shi W, Ramsay ES, Bliskovsky V, Eiden AM, Connors D, et al. The transcription factor MZF1 differentially regulates murine Mtor promoter variants linked to tumor susceptibility. J Biol Chem. 2019;294:16756–64.
Li J, Liao T, Liu H, Yuan H, Ouyang T, Wang J, et al. Hypoxic glioma stem cell-derived exosomes containing linc01060 promote progression of glioma by regulating the MZF1/c-Myc/HIF1alpha axis. Cancer Res. 2021;81:114–28.
Brix DM, Tvingsholm SA, Hansen MB, Clemmensen KB, Ohman T, Siino V, et al. Release of transcriptional repression via ErbB2-induced, SUMO-directed phosphorylation of myeloid zinc finger-1 serine 27 activates lysosome redistribution and invasion. Oncogene. 2019;38:3170–84.
Scaglioni PP, Rabellino A, Yung TM, Bernardi R, Choi S, Konstantinidou G, et al. Translation-dependent mechanisms lead to PML upregulation and mediate oncogenic K-RAS-induced cellular senescence. EMBO Mol Med. 2012;4:594–602.
Campisi J, d’Adda di, Fagagna F. Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol. 2007;8:729–40.
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.
The authors declare no competing interests.
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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