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Int J Biol Sci 2022; 18(7):2962-2979. doi:10.7150/ijbs.71283 This issue Cite

Research Paper

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

Shuai Zhang^1*, Mengru Cao^1*, Shi Yan¹, Yuechao Liu¹, Weina Fan¹, Yimeng Cui¹, Fanglin Tian¹, Ruixue Gu¹, Yaowen Cui¹, Yuning Zhan¹, Yuanyuan Sun¹, Ying Xing^1✉, Li Cai^1✉, Yang Song^2✉

1. The Fourth Department of Medical Oncology, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, 150081, China.
2. The First Department of Orthopedic Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China.
*These authors contributed equally to this work.

✉ Corresponding authors: Ying Xing, The Fourth Department of Medical Oncology, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, 150040, China. Tel.: +86 451 86298038; Fax: +86 451 86298735; E-mail: xingyingedu.cn. Li Cai, The Fourth Department of Medical Oncology, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, 150040, China. Tel.: +86 451 86298099; Fax: +86 451 86298735; E-mail: cailihrbmu.edu.cn. Yang Song, The First Department of Orthopedic Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China. Tel.: +86 451 86605046; Fax: +86 451 86605046; E-mail: songyangedu.cn. More

Abstract

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.

Keywords: TRIM44, lung adenocarcinoma, cisplatin chemoresistance, BRCA1, FLNA

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