title: A role of autophagy in PTP4A3-driven cancer progression.
abstract: Autophagy, a "self-eating" cellular process, has dual roles in promoting and suppressing tumor growth, depending on cellular context. PTP4A3/PRL-3, a plasma membrane and endosomal phosphatase, promotes multiple oncogenic processes including cell proliferation, invasion, and cancer metastasis. In this study, we demonstrate that PTP4A3 accumulates in autophagosomes upon inhibition of autophagic degradation. Expression of PTP4A3 enhances PIK3C3-BECN1-dependent autophagosome formation and accelerates LC3-I to LC3-II conversion in an ATG5-dependent manner. PTP4A3 overexpression also enhances the degradation of SQSTM1, a key autophagy substrate. These functions of PTP4A3 are dependent on its catalytic activity and prenylation-dependent membrane association. These results suggest that PTP4A3 functions to promote canonical autophagy flux. Unexpectedly, following autophagy activation, PTP4A3 serves as a novel autophagic substrate, thereby establishing a negative feedback-loop that may be required to fine-tune autophagy activity. Functionally, PTP4A3 utilizes the autophagy pathway to promote cell growth, concomitant with the activation of AKT. Clinically, from the largest ovarian cancer data set (GSE 9899, n = 285) available in GEO, high levels of expression of both PTP4A3 and autophagy genes significantly predict poor prognosis of ovarian cancer patients. These studies reveal a critical role of autophagy in PTP4A3-driven cancer progression, suggesting that autophagy could be a potential Achilles heel to block PTP4A3-mediated tumor progression in stratified patients with high expression of both PTP4A3 and autophagy genes.
authors.affiliation: Institute of Molecular and Cell Biology; A*STAR (Agency for Science, Technology and Research); Singapore; NUS Graduate School for Integrative Sciences and Engineering; National University of Singapore; Singapore.
authors.forename: Yu-Han
authors.initials: YH
authors.lastname: Huang
authors.affiliation: Institute of Molecular and Cell Biology; A*STAR (Agency for Science, Technology and Research); Singapore.
authors.forename: Abdul Qader O
authors.initials: AQ
authors.lastname: Al-Aidaroos
authors.affiliation: Institute of Molecular and Cell Biology; A*STAR (Agency for Science, Technology and Research); Singapore.
authors.forename: Hiu-Fung
authors.initials: HF
authors.lastname: Yuen
authors.affiliation: Center for Cancer Research and Cell Biology; Queen's University Belfast; Belfast UK.
authors.forename: Shu-Dong
authors.initials: SD
authors.lastname: Zhang
authors.affiliation: Department of Epidemiology and Public Health; National University of Singapore; Singapore.
authors.forename: Han-Ming
authors.initials: HM
authors.lastname: Shen
authors.affiliation: Center for Cancer Research and Cell Biology; Queen's University Belfast; Belfast UK; Current affiliation: School of Biochemistry and Immunology; Trinity College; Dublin, Ireland.
authors.forename: Ewelina
authors.initials: E
authors.lastname: Rozycka
authors.affiliation: Center for Cancer Research and Cell Biology; Queen's University Belfast; Belfast UK.
authors.forename: Cian M
authors.initials: CM
authors.lastname: McCrudden
authors.affiliation: Institute of Molecular and Cell Biology; A*STAR (Agency for Science, Technology and Research); Singapore.
authors.forename: Vinay
authors.initials: V
authors.lastname: Tergaonkar
authors.affiliation: Institute of Molecular and Cell Biology; A*STAR (Agency for Science, Technology and Research); Singapore.
authors.forename: Abhishek
authors.initials: A
authors.lastname: Gupta
authors.affiliation: Institute of Molecular and Cell Biology; A*STAR (Agency for Science, Technology and Research); Singapore.
authors.forename: You Bin
authors.initials: YB
authors.lastname: Lin
authors.affiliation: Institute of Molecular and Cell Biology; A*STAR (Agency for Science, Technology and Research); Singapore; Department of Biochemistry; Yong Loo Lin School of Medicine; National University of Singapore; Singapore.
authors.forename: Jean Paul
authors.initials: JP
authors.lastname: Thiery
authors.affiliation: Current affiliation: School of Biochemistry and Immunology; Trinity College; Dublin, Ireland.
authors.forename: James T
authors.initials: JT
authors.lastname: Murray
authors.affiliation: Institute of Molecular and Cell Biology; A*STAR (Agency for Science, Technology and Research); Singapore; Department of Biochemistry; Yong Loo Lin School of Medicine; National University of Singapore; Singapore.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zeng
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D055162:Biocatalysis / Q000187:drug effects; D016466:CHO Cells; D018797:Cell Cycle Proteins / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002738:Chloroquine / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D010588:Phagosomes / Q000187:drug effects / Q000378:metabolism; D054876:Prenylation / Q000187:drug effects; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D000071456:Sequestosome-1 Protein; D013379:Substrate Specificity / Q000187:drug effects; D016019:Survival Analysis
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C477012:MAP1LC3A protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D002738:Chloroquine; C490198:PTP4A1 protein, human; C484730:PTP4A3 protein, human; D017027:Protein Tyrosine Phosphatases
keywords: BECN1; PIK3C3; PTP4A3; cancer progression; mammalian autophagy regulation; prognosis marker