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The PEST motif is responsible for particular posttranslational modifications (PTMs). These PTMs impart distinct properties to PEST\u2010NPs that are responsible for their activation\/inhibition, intracellular localization, and stability\/degradation. PEST\u2010NPs participate in cancer metabolism, immunity, and protein transcription as oncogenes or as tumor suppressors. Gene\u2010based therapeutics are getting the attention of researchers because of their cell specificity. PEST\u2010NPs are good targets to explore as cancer therapeutics. Insights into PTMs of PEST\u2010NPs demonstrate that these proteins not only interact with each other but also recruit other proteins to\/from their active site to promote\/inhibit tumors. Thus, the role of PEST\u2010NPs in cancer biology is multivariate. It is hard to obtain therapeutic objectives with single gene therapy. An especially designed combination gene therapy might be a promising strategy in cancer treatment. This review highlights the multifaceted behavior of PEST\u2010NPs in cancer biology. We have summarized a number of studies to address the influence of structure and PEST\u2010mediated PTMs on activation, localization, stability, and protein\u2013protein interactions of PEST\u2010NPs. We also recommend researchers to adopt a pragmatic approach in gene\u2010based cancer therapy.<\/jats:p>","DOI":"10.1002\/jcp.30011","type":"journal-article","created":{"date-parts":[[2020,8,26]],"date-time":"2020-08-26T03:13:40Z","timestamp":1598411620000},"page":"1658-1676","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Multifaceted behavior of PEST sequence enriched nuclear proteins in cancer biology and role in gene therapy"],"prefix":"10.1002","volume":"236","author":[{"given":"Muhammad","family":"Sarfraz","sequence":"first","affiliation":[{"name":"Henan International Joint Laboratory for Nuclear Protein Regulation &amp; Kaifeng Key Laboratory of Infectious Diseases and Bio\u2010safety, School of Basic Medical Sciences Henan University College of Medicine  Kaifeng Henan China"},{"name":"Faculty of Pharmacy The University of Lahore  Lahore Punjab Pakistan"},{"name":"Kaifeng Municipal Key Laboratory of Cell Signal Transduction, Henan Provincial Engineering Centre for Tumor Molecular Medicine Henan University  Kaifeng Henan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Attia","family":"Afzal","sequence":"additional","affiliation":[{"name":"Henan International Joint Laboratory for Nuclear Protein Regulation &amp; Kaifeng Key Laboratory of Infectious Diseases and Bio\u2010safety, School of Basic Medical Sciences Henan University College of Medicine  Kaifeng Henan China"},{"name":"Faculty of Pharmacy The University of Lahore  Lahore Punjab Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saadullah","family":"Khattak","sequence":"additional","affiliation":[{"name":"Henan International Joint Laboratory for Nuclear Protein Regulation &amp; Kaifeng Key Laboratory of Infectious Diseases and Bio\u2010safety, School of Basic Medical Sciences Henan University College of Medicine  Kaifeng Henan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Umair A. 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