Cargando…

TRIM44 promotes BRCA1 functions in HR repair to induce Cisplatin Chemoresistance in Lung Adenocarcinoma by Deubiquitinating FLNA

Tripartite motif-containing 44 (TRIM44) has recently been implicated in various pathological processes in numerous cancers, including lung adenocarcinoma (LUAD); however, its functional roles in chemoresistance are poorly understood. Herein, TRIM44 knockdown sensitized LUAD cells to cisplatin and en...

Descripción completa

Detalles Bibliográficos
Autores principales: Zhang, Shuai, Cao, Mengru, Yan, Shi, Liu, Yuechao, Fan, Weina, Cui, Yimeng, Tian, Fanglin, Gu, Ruixue, Cui, Yaowen, Zhan, Yuning, Sun, Yuanyuan, Xing, Ying, Cai, Li, Song, Yang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ivyspring International Publisher 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9066100/
https://www.ncbi.nlm.nih.gov/pubmed/35541909
http://dx.doi.org/10.7150/ijbs.71283
_version_ 1784699732702003200
author Zhang, Shuai
Cao, Mengru
Yan, Shi
Liu, Yuechao
Fan, Weina
Cui, Yimeng
Tian, Fanglin
Gu, Ruixue
Cui, Yaowen
Zhan, Yuning
Sun, Yuanyuan
Xing, Ying
Cai, Li
Song, Yang
author_facet Zhang, Shuai
Cao, Mengru
Yan, Shi
Liu, Yuechao
Fan, Weina
Cui, Yimeng
Tian, Fanglin
Gu, Ruixue
Cui, Yaowen
Zhan, Yuning
Sun, Yuanyuan
Xing, Ying
Cai, Li
Song, Yang
author_sort Zhang, Shuai
collection PubMed
description Tripartite motif-containing 44 (TRIM44) has recently been implicated in various pathological processes in numerous cancers, including lung adenocarcinoma (LUAD); however, its functional roles in chemoresistance are poorly understood. Herein, TRIM44 knockdown sensitized LUAD cells to cisplatin and enhanced cisplatin-induced apoptosis. Microarray analysis indicated that the “Role of BRCA1 in DNA damage” and the BRCA1 gene expression were positively regulated by TRIM44, which was further verified by immunofluorescence, qRT-PCR, and Western blotting. BRCA1 depletion effectively abolished TRIM44-modulated cisplatin resistance and regulation of homologous recombination (HR) repair. Interestingly, TRIM44 interacted with FLNA, an upstream regulator of BRCA1 as specified by STRING V 11.5, and facilitated its stability and deubiquitination. FLNA was also found to be required for the functions of TRIM44 in drug resistance. Using animal models, overexpression of TRIM44 was shown to confer resistance to cisplatin in a BRCA1- and FLNA-dependent manner. TRIM44 expression levels in tissues from cisplatin-resistant LUAD patients were significantly higher than those in tissues from cisplatin-sensitive LUAD patients. Collectively, our study results demonstrate that the TRIM44/FLNA/BRCA1 axis is involved in cisplatin chemoresistance, providing potential therapeutic targets for LUAD patients with cisplatin resistance.
format Online
Article
Text
id pubmed-9066100
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Ivyspring International Publisher
record_format MEDLINE/PubMed
spelling pubmed-90661002022-05-09 TRIM44 promotes BRCA1 functions in HR repair to induce Cisplatin Chemoresistance in Lung Adenocarcinoma by Deubiquitinating FLNA Zhang, Shuai Cao, Mengru Yan, Shi Liu, Yuechao Fan, Weina Cui, Yimeng Tian, Fanglin Gu, Ruixue Cui, Yaowen Zhan, Yuning Sun, Yuanyuan Xing, Ying Cai, Li Song, Yang Int J Biol Sci Research Paper Tripartite motif-containing 44 (TRIM44) has recently been implicated in various pathological processes in numerous cancers, including lung adenocarcinoma (LUAD); however, its functional roles in chemoresistance are poorly understood. Herein, TRIM44 knockdown sensitized LUAD cells to cisplatin and enhanced cisplatin-induced apoptosis. Microarray analysis indicated that the “Role of BRCA1 in DNA damage” and the BRCA1 gene expression were positively regulated by TRIM44, which was further verified by immunofluorescence, qRT-PCR, and Western blotting. BRCA1 depletion effectively abolished TRIM44-modulated cisplatin resistance and regulation of homologous recombination (HR) repair. Interestingly, TRIM44 interacted with FLNA, an upstream regulator of BRCA1 as specified by STRING V 11.5, and facilitated its stability and deubiquitination. FLNA was also found to be required for the functions of TRIM44 in drug resistance. Using animal models, overexpression of TRIM44 was shown to confer resistance to cisplatin in a BRCA1- and FLNA-dependent manner. TRIM44 expression levels in tissues from cisplatin-resistant LUAD patients were significantly higher than those in tissues from cisplatin-sensitive LUAD patients. Collectively, our study results demonstrate that the TRIM44/FLNA/BRCA1 axis is involved in cisplatin chemoresistance, providing potential therapeutic targets for LUAD patients with cisplatin resistance. Ivyspring International Publisher 2022-04-18 /pmc/articles/PMC9066100/ /pubmed/35541909 http://dx.doi.org/10.7150/ijbs.71283 Text en © The author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
spellingShingle Research Paper
Zhang, Shuai
Cao, Mengru
Yan, Shi
Liu, Yuechao
Fan, Weina
Cui, Yimeng
Tian, Fanglin
Gu, Ruixue
Cui, Yaowen
Zhan, Yuning
Sun, Yuanyuan
Xing, Ying
Cai, Li
Song, Yang
TRIM44 promotes BRCA1 functions in HR repair to induce Cisplatin Chemoresistance in Lung Adenocarcinoma by Deubiquitinating FLNA
title TRIM44 promotes BRCA1 functions in HR repair to induce Cisplatin Chemoresistance in Lung Adenocarcinoma by Deubiquitinating FLNA
title_full TRIM44 promotes BRCA1 functions in HR repair to induce Cisplatin Chemoresistance in Lung Adenocarcinoma by Deubiquitinating FLNA
title_fullStr TRIM44 promotes BRCA1 functions in HR repair to induce Cisplatin Chemoresistance in Lung Adenocarcinoma by Deubiquitinating FLNA
title_full_unstemmed TRIM44 promotes BRCA1 functions in HR repair to induce Cisplatin Chemoresistance in Lung Adenocarcinoma by Deubiquitinating FLNA
title_short TRIM44 promotes BRCA1 functions in HR repair to induce Cisplatin Chemoresistance in Lung Adenocarcinoma by Deubiquitinating FLNA
title_sort trim44 promotes brca1 functions in hr repair to induce cisplatin chemoresistance in lung adenocarcinoma by deubiquitinating flna
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9066100/
https://www.ncbi.nlm.nih.gov/pubmed/35541909
http://dx.doi.org/10.7150/ijbs.71283
work_keys_str_mv AT zhangshuai trim44promotesbrca1functionsinhrrepairtoinducecisplatinchemoresistanceinlungadenocarcinomabydeubiquitinatingflna
AT caomengru trim44promotesbrca1functionsinhrrepairtoinducecisplatinchemoresistanceinlungadenocarcinomabydeubiquitinatingflna
AT yanshi trim44promotesbrca1functionsinhrrepairtoinducecisplatinchemoresistanceinlungadenocarcinomabydeubiquitinatingflna
AT liuyuechao trim44promotesbrca1functionsinhrrepairtoinducecisplatinchemoresistanceinlungadenocarcinomabydeubiquitinatingflna
AT fanweina trim44promotesbrca1functionsinhrrepairtoinducecisplatinchemoresistanceinlungadenocarcinomabydeubiquitinatingflna
AT cuiyimeng trim44promotesbrca1functionsinhrrepairtoinducecisplatinchemoresistanceinlungadenocarcinomabydeubiquitinatingflna
AT tianfanglin trim44promotesbrca1functionsinhrrepairtoinducecisplatinchemoresistanceinlungadenocarcinomabydeubiquitinatingflna
AT guruixue trim44promotesbrca1functionsinhrrepairtoinducecisplatinchemoresistanceinlungadenocarcinomabydeubiquitinatingflna
AT cuiyaowen trim44promotesbrca1functionsinhrrepairtoinducecisplatinchemoresistanceinlungadenocarcinomabydeubiquitinatingflna
AT zhanyuning trim44promotesbrca1functionsinhrrepairtoinducecisplatinchemoresistanceinlungadenocarcinomabydeubiquitinatingflna
AT sunyuanyuan trim44promotesbrca1functionsinhrrepairtoinducecisplatinchemoresistanceinlungadenocarcinomabydeubiquitinatingflna
AT xingying trim44promotesbrca1functionsinhrrepairtoinducecisplatinchemoresistanceinlungadenocarcinomabydeubiquitinatingflna
AT caili trim44promotesbrca1functionsinhrrepairtoinducecisplatinchemoresistanceinlungadenocarcinomabydeubiquitinatingflna
AT songyang trim44promotesbrca1functionsinhrrepairtoinducecisplatinchemoresistanceinlungadenocarcinomabydeubiquitinatingflna