Cargando…

Novel STAT3 Inhibitor LDOC1 Targets Phospho-JAK2 for Degradation by Interacting with LNX1 and Regulates the Aggressiveness of Lung Cancer

Meta-analysis revealed that Leucine Zipper Down-Regulated In Cancer 1 (LDOC1) increased methylation more in people with lung tumors than in those who were healthy and never smoked. Quantitative methylation-specific PCR revealed that cigarette smoke condensate (CSC) exposure drives LDOC1 promoter hyp...

Descripción completa

Detalles Bibliográficos
Autores principales: Lee, Chia-Huei, Yang, Ji-Rui, Chen, Chih-Yu, Tsai, Ming-Hsien, Hung, Pin-Feng, Chen, Shin-Jih, Chiang, Shang-Lun, Chang, Han, Lin, Pinpin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6356782/
https://www.ncbi.nlm.nih.gov/pubmed/30634502
http://dx.doi.org/10.3390/cancers11010063
_version_ 1783391635309068288
author Lee, Chia-Huei
Yang, Ji-Rui
Chen, Chih-Yu
Tsai, Ming-Hsien
Hung, Pin-Feng
Chen, Shin-Jih
Chiang, Shang-Lun
Chang, Han
Lin, Pinpin
author_facet Lee, Chia-Huei
Yang, Ji-Rui
Chen, Chih-Yu
Tsai, Ming-Hsien
Hung, Pin-Feng
Chen, Shin-Jih
Chiang, Shang-Lun
Chang, Han
Lin, Pinpin
author_sort Lee, Chia-Huei
collection PubMed
description Meta-analysis revealed that Leucine Zipper Down-Regulated In Cancer 1 (LDOC1) increased methylation more in people with lung tumors than in those who were healthy and never smoked. Quantitative methylation-specific PCR revealed that cigarette smoke condensate (CSC) exposure drives LDOC1 promoter hypermethylation and silence in human bronchial cells. Immunohistochemistry studies showed that LDOC1 downregulation is associated with poor survival of patients with lung cancer. Loss and gain of LDOC1 functions enhanced and attenuated aggressive phenotypes in lung adenocarcinoma A549 and non–small cell lung carcinoma H1299 cell lines, respectively. We found that LDOC1 deficiency led to reinforcing a reciprocal loop of IL-6/JAK2/STAT3, through which LDOC1 mediates the cancer progression. LDOC1 knockdown considerably augmented tumorigenesis and the phosphorylation of JAK2 and STAT3 in vivo. Results from immunoprecipitation and immunofluorescent confocal microscopy indicated that LDOC1 negatively regulates JAK2 activity by forming multiple protein complexes with pJAK2 and E3 ubiquitin-protein ligase LNX1, and in turn, LDOC1 targets pJAK2 to cause ubiquitin-dependent proteasomal degradation. LDOC1 deficiency attenuates the interactions between LNX1 and pJAK2, leading to ineffective ubiquitination of pJAK2, which activates STAT3. Overall, our results elucidated a crucial role of LDOC1 in lung cancer and revealed how LDOC1 acts as a bridge between tobacco exposure and the IL-6/JAK2/STAT3 loop in this human malignancy.
format Online
Article
Text
id pubmed-6356782
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-63567822019-02-05 Novel STAT3 Inhibitor LDOC1 Targets Phospho-JAK2 for Degradation by Interacting with LNX1 and Regulates the Aggressiveness of Lung Cancer Lee, Chia-Huei Yang, Ji-Rui Chen, Chih-Yu Tsai, Ming-Hsien Hung, Pin-Feng Chen, Shin-Jih Chiang, Shang-Lun Chang, Han Lin, Pinpin Cancers (Basel) Article Meta-analysis revealed that Leucine Zipper Down-Regulated In Cancer 1 (LDOC1) increased methylation more in people with lung tumors than in those who were healthy and never smoked. Quantitative methylation-specific PCR revealed that cigarette smoke condensate (CSC) exposure drives LDOC1 promoter hypermethylation and silence in human bronchial cells. Immunohistochemistry studies showed that LDOC1 downregulation is associated with poor survival of patients with lung cancer. Loss and gain of LDOC1 functions enhanced and attenuated aggressive phenotypes in lung adenocarcinoma A549 and non–small cell lung carcinoma H1299 cell lines, respectively. We found that LDOC1 deficiency led to reinforcing a reciprocal loop of IL-6/JAK2/STAT3, through which LDOC1 mediates the cancer progression. LDOC1 knockdown considerably augmented tumorigenesis and the phosphorylation of JAK2 and STAT3 in vivo. Results from immunoprecipitation and immunofluorescent confocal microscopy indicated that LDOC1 negatively regulates JAK2 activity by forming multiple protein complexes with pJAK2 and E3 ubiquitin-protein ligase LNX1, and in turn, LDOC1 targets pJAK2 to cause ubiquitin-dependent proteasomal degradation. LDOC1 deficiency attenuates the interactions between LNX1 and pJAK2, leading to ineffective ubiquitination of pJAK2, which activates STAT3. Overall, our results elucidated a crucial role of LDOC1 in lung cancer and revealed how LDOC1 acts as a bridge between tobacco exposure and the IL-6/JAK2/STAT3 loop in this human malignancy. MDPI 2019-01-09 /pmc/articles/PMC6356782/ /pubmed/30634502 http://dx.doi.org/10.3390/cancers11010063 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Lee, Chia-Huei
Yang, Ji-Rui
Chen, Chih-Yu
Tsai, Ming-Hsien
Hung, Pin-Feng
Chen, Shin-Jih
Chiang, Shang-Lun
Chang, Han
Lin, Pinpin
Novel STAT3 Inhibitor LDOC1 Targets Phospho-JAK2 for Degradation by Interacting with LNX1 and Regulates the Aggressiveness of Lung Cancer
title Novel STAT3 Inhibitor LDOC1 Targets Phospho-JAK2 for Degradation by Interacting with LNX1 and Regulates the Aggressiveness of Lung Cancer
title_full Novel STAT3 Inhibitor LDOC1 Targets Phospho-JAK2 for Degradation by Interacting with LNX1 and Regulates the Aggressiveness of Lung Cancer
title_fullStr Novel STAT3 Inhibitor LDOC1 Targets Phospho-JAK2 for Degradation by Interacting with LNX1 and Regulates the Aggressiveness of Lung Cancer
title_full_unstemmed Novel STAT3 Inhibitor LDOC1 Targets Phospho-JAK2 for Degradation by Interacting with LNX1 and Regulates the Aggressiveness of Lung Cancer
title_short Novel STAT3 Inhibitor LDOC1 Targets Phospho-JAK2 for Degradation by Interacting with LNX1 and Regulates the Aggressiveness of Lung Cancer
title_sort novel stat3 inhibitor ldoc1 targets phospho-jak2 for degradation by interacting with lnx1 and regulates the aggressiveness of lung cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6356782/
https://www.ncbi.nlm.nih.gov/pubmed/30634502
http://dx.doi.org/10.3390/cancers11010063
work_keys_str_mv AT leechiahuei novelstat3inhibitorldoc1targetsphosphojak2fordegradationbyinteractingwithlnx1andregulatestheaggressivenessoflungcancer
AT yangjirui novelstat3inhibitorldoc1targetsphosphojak2fordegradationbyinteractingwithlnx1andregulatestheaggressivenessoflungcancer
AT chenchihyu novelstat3inhibitorldoc1targetsphosphojak2fordegradationbyinteractingwithlnx1andregulatestheaggressivenessoflungcancer
AT tsaiminghsien novelstat3inhibitorldoc1targetsphosphojak2fordegradationbyinteractingwithlnx1andregulatestheaggressivenessoflungcancer
AT hungpinfeng novelstat3inhibitorldoc1targetsphosphojak2fordegradationbyinteractingwithlnx1andregulatestheaggressivenessoflungcancer
AT chenshinjih novelstat3inhibitorldoc1targetsphosphojak2fordegradationbyinteractingwithlnx1andregulatestheaggressivenessoflungcancer
AT chiangshanglun novelstat3inhibitorldoc1targetsphosphojak2fordegradationbyinteractingwithlnx1andregulatestheaggressivenessoflungcancer
AT changhan novelstat3inhibitorldoc1targetsphosphojak2fordegradationbyinteractingwithlnx1andregulatestheaggressivenessoflungcancer
AT linpinpin novelstat3inhibitorldoc1targetsphosphojak2fordegradationbyinteractingwithlnx1andregulatestheaggressivenessoflungcancer