Tumor Suppressors Having Oncogenic Functions: The Double Agents

Overview

Journal Cells

Publisher MDPI

Specialties Biochemistry
Biophysics
Cell Biology
Molecular Biology

Date 2021 Jan 5

PMID 33396222

Citations 39

Authors

Neerajana Datta

Shrabastee Chakraborty

Malini Basu

Mrinal K Ghosh

Affiliations

Soon will be listed here.

Abstract

Cancer progression involves multiple genetic and epigenetic events, which involve gain-of-functions of oncogenes and loss-of-functions of tumor suppressor genes. Classical tumor suppressor genes are recessive in nature, anti-proliferative, and frequently found inactivated or mutated in cancers. However, extensive research over the last few years have elucidated that certain tumor suppressor genes do not conform to these standard definitions and might act as "double agents", playing contrasting roles in vivo in cells, where either due to haploinsufficiency, epigenetic hypermethylation, or due to involvement with multiple genetic and oncogenic events, they play an enhanced proliferative role and facilitate the pathogenesis of cancer. This review discusses and highlights some of these exceptions; the genetic events, cellular contexts, and mechanisms by which four important tumor suppressors-pRb, PTEN, FOXO, and PML display their oncogenic potentials and pro-survival traits in cancer.

Citing Articles

Amyloids in bladder cancer hijack cancer-related proteins and are positive correlated to tumor stage.

Alem D, Garcia-Lavina C, Garagorry F, Centurion D, Farias J, Pazos-Espinosa H Sci Rep. 2025; 15(1):4393.

PMID: 39910105 PMC: 11799152. DOI: 10.1038/s41598-025-88307-7.

The interplay of p16INK4a and non-coding RNAs: bridging cellular senescence, aging, and cancer.

Balaraman A, Afzal M, Moglad E, Babu M, Priya G, Bansal P Biogerontology. 2025; 26(2):50.

PMID: 39907830 DOI: 10.1007/s10522-025-10194-2.

Sociobiology meets oncology: unraveling altruistic cooperation in cancer cells and its implications.

Bin Masroni M, Koay E, Lee V, Ng S, Tan S, Tan K Exp Mol Med. 2025; 57(1):30-40.

PMID: 39774289 PMC: 11799181. DOI: 10.1038/s12276-024-01387-9.

Re-evaluation of the relationship between PrPc expression and patient prognosis in primary esophageal squamous cell carcinoma and primary hepatocellular carcinoma.

Zhang C, Ran F, Du L, Cao Y, Chen H, Chen Q Sci Rep. 2024; 14(1):31122.

PMID: 39732816 PMC: 11682241. DOI: 10.1038/s41598-024-82398-4.

Integrated analysis of cell cycle and p53 signaling pathways related genes in breast, colorectal, lung, and pancreatic cancers: implications for prognosis and drug sensitivity for therapeutic potential.

Khan J, Ghosh P, Bajpai U, Dwivedi K, Saluja D Discov Oncol. 2024; 15(1):832.

PMID: 39715832 PMC: 11666898. DOI: 10.1007/s12672-024-01712-8.

References

Donzelli S, Fontemaggi G, Fazi F, Di Agostino S, Padula F, Biagioni F . MicroRNA-128-2 targets the transcriptional repressor E2F5 enhancing mutant p53 gain of function. Cell Death Differ. 2011; 19(6):1038-48. PMC: 3354056. DOI: 10.1038/cdd.2011.190. View

Moelling K, Schad K, Bosse M, Zimmermann S, Schweneker M . Regulation of Raf-Akt Cross-talk. J Biol Chem. 2002; 277(34):31099-106. DOI: 10.1074/jbc.M111974200. View

Liu H, Song Y, Qiu H, Liu Y, Luo K, Yi Y . Downregulation of FOXO3a by DNMT1 promotes breast cancer stem cell properties and tumorigenesis. Cell Death Differ. 2019; 27(3):966-983. PMC: 7206060. DOI: 10.1038/s41418-019-0389-3. View

Vidal A, Zacharoulis S, Guo W, Shaffer D, Giancotti F, Bramley A . p130Rb2 and p27kip1 cooperate to control mobilization of angiogenic progenitors from the bone marrow. Proc Natl Acad Sci U S A. 2005; 102(19):6890-5. PMC: 1088064. DOI: 10.1073/pnas.0405823102. View

Gaiddon C, Lokshin M, Ahn J, Zhang T, Prives C . A subset of tumor-derived mutant forms of p53 down-regulate p63 and p73 through a direct interaction with the p53 core domain. Mol Cell Biol. 2001; 21(5):1874-87. PMC: 86759. DOI: 10.1128/MCB.21.5.1874-1887.2001. View

Bellodi C, Kindle K, Bernassola F, Dinsdale D, Cossarizza A, Melino G . Cytoplasmic function of mutant promyelocytic leukemia (PML) and PML-retinoic acid receptor-alpha. J Biol Chem. 2006; 281(20):14465-73. DOI: 10.1074/jbc.M600457200. View

Zhu J, Sammons M, Donahue G, Dou Z, Vedadi M, Getlik M . Gain-of-function p53 mutants co-opt chromatin pathways to drive cancer growth. Nature. 2015; 525(7568):206-11. PMC: 4568559. DOI: 10.1038/nature15251. View

Zhang X, Pfeiffer H, Mellert H, Stanek T, Sussman R, Kumari A . Inhibition of the single downstream target BAG1 activates the latent apoptotic potential of MYC. Mol Cell Biol. 2011; 31(24):5037-45. PMC: 3233020. DOI: 10.1128/MCB.06297-11. View

Jin G, Kondo E, Miyake T, Shibata M, Takashima T, Liu Y . Expression and intracellular localization of FKHRL1 in mammary gland neoplasms. Acta Med Okayama. 2004; 58(4):197-205. DOI: 10.18926/AMO/32088. View

10.

Zundel W, Schindler C, Koong A, Kaper F, Chen E, Gottschalk A . Loss of PTEN facilitates HIF-1-mediated gene expression. Genes Dev. 2000; 14(4):391-6. PMC: 316386. View

11.

Datta N, Islam S, Chatterjee U, Chatterjee S, Panda C, Ghosh M . Promyelocytic Leukemia (PML) gene regulation: implication towards curbing oncogenesis. Cell Death Dis. 2019; 10(9):656. PMC: 6736969. DOI: 10.1038/s41419-019-1889-2. View

12.

Wu Z, Zheng S, Li Z, Tan J, Yu Q . E2F1 suppresses Wnt/β-catenin activity through transactivation of β-catenin interacting protein ICAT. Oncogene. 2011; 30(37):3979-84. DOI: 10.1038/onc.2011.129. View

13.

Pollina E, Brunet A . Epigenetic regulation of aging stem cells. Oncogene. 2011; 30(28):3105-26. DOI: 10.1038/onc.2011.45. View

14.

Naka K, Hoshii T, Muraguchi T, Tadokoro Y, Ooshio T, Kondo Y . TGF-beta-FOXO signalling maintains leukaemia-initiating cells in chronic myeloid leukaemia. Nature. 2010; 463(7281):676-80. DOI: 10.1038/nature08734. View

15.

Wegiel B, Bjartell A, Ekberg J, Gadaleanu V, Brunhoff C, Persson J . A role for cyclin A1 in mediating the autocrine expression of vascular endothelial growth factor in prostate cancer. Oncogene. 2005; 24(42):6385-93. DOI: 10.1038/sj.onc.1208795. View

16.

Sun J, Fu S, Zhong W, Huang H . PML overexpression inhibits proliferation and promotes the osteogenic differentiation of human mesenchymal stem cells. Oncol Rep. 2013; 30(6):2785-94. DOI: 10.3892/or.2013.2786. View

17.

Bellodi C, Kindle K, Bernassola F, Cossarizza A, Dinsdale D, Melino G . A cytoplasmic PML mutant inhibits p53 function. Cell Cycle. 2006; 5(22):2688-92. DOI: 10.4161/cc.5.22.3504. View

18.

Ponente M, Campanini L, Cuttano R, Piunti A, Delledonne G, Coltella N . PML promotes metastasis of triple-negative breast cancer through transcriptional regulation of HIF1A target genes. JCI Insight. 2017; 2(4):e87380. PMC: 5313064. DOI: 10.1172/jci.insight.87380. View

19.

Wang L, Wang W, Zhang Y, Guo S, Zhang J, Li Q . Epigenetic and genetic alterations of PTEN in hepatocellular carcinoma. Hepatol Res. 2007; 37(5):389-96. DOI: 10.1111/j.1872-034X.2007.00042.x. View

20.

Das N, Datta N, Chatterjee U, Ghosh M . Estrogen receptor alpha transcriptionally activates casein kinase 2 alpha: A pivotal regulator of promyelocytic leukaemia protein (PML) and AKT in oncogenesis. Cell Signal. 2016; 28(6):675-87. DOI: 10.1016/j.cellsig.2016.03.007. View