TMEM120B strengthens breast cancer cell stemness and accelerates chemotherapy resistance via β1-integrin/FAK-TAZ-mTOR signaling axis by binding to MYH9

• DOI: 10.1186/s13058-024-01802-z
• Publication Date: 2024-03-19T10:05:12Z
• Authors: Ran Hu; Yu Cao; Yuanyuan Wang; Tingting Zhao; Kaibo Yang; Mingwei Fan; Mengyao Guan; Yuekang Hou; Jiao Ying; Xiaowen Ma; Ning Deng; Xun Sun; Yong Zhang; Xiupeng Zhang
• Keywords: Ovarian Neoplasms; 0303 health sciences; Myosin Heavy Chains; Research; Integrin beta1; TOR Serine-Threonine Kinases; Focal adhension kinase; Neoplasms. Tumors. Oncology. Including cancer and carcinogens; Breast Neoplasms; MYH9; Mice; 03 medical and health sciences; Breast cancer; Cell Line, Tumor; Humans; Animals; Female; TMEM120B; Stemness; RC254-282; Cell Proliferation

Abstract Background Breast cancer stem cell (CSC) expansion results in tumor progression and chemoresistance; however, the modulation of CSC pluripotency remains unexplored. Transmembrane protein 120B (TMEM120B) is a newly discovered expressed human tissues, especially malignant tissues; its role has not been studied. This study aimed to determine TMEM120B transcriptional coactivator with PDZ-binding motif (TAZ)-mediated chemotherapy resistance. Methods Both bioinformatics analysis immunohistochemistry assays were performed examine expression patterns lung, breast, gastric, colon, ovarian cancers. Clinicopathological factors overall survival also evaluated. Next, colony formation assay, MTT EdU transwell wound healing flow cytometric analysis, sphere western blotting mouse xenograft model RNA-sequencing immunofluorescence reverse transcriptase-polymerase chain reaction investigate effect interaction on proliferation, invasion, stemness, sensitivity, integrin/FAK/TAZ/mTOR activation. Further, liquid chromatography–tandem mass spectrometry GST pull-down immunoprecipitation evaluate interactions between TMEM120B, myosin heavy 9 (MYH9), CUL9. Results was elevated positively correlated advanced TNM stage, lymph node metastasis, poor prognosis. Overexpression promoted breast stemness by activating TAZ-mTOR signaling. directly bound coil-coil domain MYH9, which accelerated assembly focal adhesions (FAs) facilitated translocation TAZ. Furthermore, stabilized MYH9 preventing degradation CUL9 ubiquitin-dependent manner. enhanced resistance docetaxel doxorubicin. Conversely, overexpression TMEM120B-∆CCD delayed FAs, suppressed signaling, abrogated patients treatment outcomes (Miller/Payne grades 1–2) than those better 3–5). Conclusions Our reveals that degradation. activated β1-integrin/FAK-TAZ-mTOR signaling axis, maintaining accelerating