Transcription factor ATMIN facilitates chemoresistance in nasopharyngeal carcinoma

• Published in: Cell death & disease Vol. 15; no. 2; pp. 112 - 11
• Main Authors: Fang, Xue-Liang, Li, Qing-Jie, Lin, Jia-Yi, Huang, Cheng-Long, Huang, Sheng-Yan, Tan, Xi-Rong, He, Shi-Wei, Zhu, Xun-Hua, Li, Jun-Yan, Gong, Sha, Qiao, Han, Li, Ying-Qin, Liu, Na, Ma, Jun, Zhao, Yin, Tang, Ling-Long
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 06.02.2024; Springer Nature B.V; Nature Publishing Group
• Subjects: 13/109; 13/89; 14/63; 38/91; 5-Fluorouracil; 631/67/1059/2326; 631/67/1536; 96/47; Antibodies; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Cell death; Cell growth; Cell proliferation; Chemoradiotherapy - methods; Chemoresistance; Chemotherapy; Cisplatin; Cisplatin - therapeutic use; DNA microarrays; Docetaxel - therapeutic use; Drug Resistance, Neoplasm; Fluorouracil - therapeutic use; Gene expression; Humans; Immunology; Lck protein; Life Sciences; Mass spectroscopy; Molecular modelling; Nasopharyngeal carcinoma; Nasopharyngeal Carcinoma - pathology; Nasopharyngeal Neoplasms - pathology; Therapeutic targets; Throat cancer; Transcription factors; Transcription Factors - therapeutic use; Ubiquitin Thiolesterase
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-024-06496-x

Despite that the docectaxel-cisplatin-5-fluorouracil (TPF) induction chemotherapy has greatly improved patients’ survival and became the first-line treatment for advanced nasopharyngeal carcinoma (NPC), not all patients could benefit from this therapy. The mechanism underlying the TPF chemoresistance remains unclear. Here, by analyzing gene-expression microarray data and survival of patients who received TPF chemotherapy, we identify transcription factor ATMIN as a chemoresistance gene in response to TPF chemotherapy in NPC. Mass spectrometry and Co-IP assays reveal that USP10 deubiquitinates and stabilizes ATMIN protein, resulting the high-ATMIN expression in NPC. Knockdown of ATMIN suppresses the cell proliferation and facilitates the docetaxel-sensitivity of NPC cells both in vitro and in vivo, while overexpression of ATMIN exerts the opposite effect. Mechanistically, ChIP-seq combined with RNA-seq analysis suggests that ATMIN is associated with the cell death signaling and identifies ten candidate target genes of ATMIN. We further confirm that ATMIN transcriptionally activates the downstream target gene LCK and stabilizes it to facilitate cell proliferation and docetaxel resistance. Taken together, our findings broaden the insight into the molecular mechanism of chemoresistance in NPC, and the USP10-ATMIN-LCK axis provides potential therapeutic targets for the management of NPC.