NMI inhibits cancer stem cell traits by downregulating hTERT in breast cancer

Abstract

N-myc and STAT interactor (NMI) has been proved to bind to different transcription factors to regulate a variety of signaling mechanisms including DNA damage, cell cycle and epithelial–mesenchymal transition. However, the role of NMI in the regulation of cancer stem cells (CSCs) remains poorly understood. In this study, we investigated the regulation of NMI on CSCs traits in breast cancer and uncovered the underlying molecular mechanisms. We found that NMI was lowly expressed in breast cancer stem cells (BCSCs)-enriched populations. Knockdown of NMI promoted CSCs traits while its overexpression inhibited CSCs traits, including the expression of CSC-related markers, the number of CD44+CD24− cell populations and the ability of mammospheres formation. We also found that NMI-mediated regulation of BCSCs traits was at least partially realized through the modulation of hTERT signaling. NMI knockdown upregulated hTERT expression while its overexpression downregulated hTERT in breast cancer cells, and the changes in CSCs traits and cell invasion ability mediated by NMI were rescued by hTERT. The in vivo study also validated that NMI knockdown promoted breast cancer growth by upregulating hTERT signaling in a mouse model. Moreover, further analyses for the clinical samples demonstrated that NMI expression was negatively correlated with hTERT expression and the low NMI/high hTERT expression was associated with the worse status of clinical TNM stages in breast cancer patients. Furthermore, we demonstrated that the interaction of YY1 protein with NMI and its involvement in NMI-mediated transcriptional regulation of hTERT in breast cancer cells. Collectively, our results provide new insights into understanding the regulatory mechanism of CSCs and suggest that the NMI-YY1-hTERT signaling axis may be a potential therapeutic target for breast cancers.

Single-Cell Tracking of Breast Cancer Cells Enables Prediction of Sphere Formation from Early Cell Divisions

“…Our single-cell tracking allowed us to find values that minimize both these factors. The values we calculated for MCF-7 cells conform very closely to what many in the field have chosen to employ ( Choi et al., 2017 , Feng et al., 2017 , Morata-Tarifa et al., 2016 ). T47D spheres proved to be much smaller and slower growing.…”

The prognostic significance of hTERT overexpression in cancers

“…Recent studies have found that hTERT does not depend on its telomere-lengthening function or its telomerase activity to promote cancer cell growth and metastasis. [43] Liu et al [44] reported that hTERT interacts with β-catenin and promotes the epithelial–mesenchymal transition and stem cell-like traits in cancer cells. Hu et al demonstrated that the hTERT-MDM2 complex enhances ITGB1 expression and ultimately promotes cancer cell metastasis.…”

Conditional knockout of N-Myc and STAT interactor disrupts normal mammary development and enhances metastatic ability of mammary tumors

“…Nmi impacts multiple signaling pathways in a context-dependent manner [ 3 , 20 ]. In particular, recent work from Zhao et al shows divergent results in hepatocellular carcinoma where knockdown of Nmi may inhibit pulmonary metastasis, an interesting observation that highlights the cell and tumor type-specific role of Nmi in cancer [ 21 ].…”