The RNA-binding protein CMSS1 promotes the progression of non-small cell lung cancer by regulating the telomerase protein subunit hTERT.

AIMS

High telomerase activity has been detected in over 85 % of tumors, with the activation of hTERT being the most crucial mechanism for re-establishing telomerase activity. Activation of hTERT maintains telomere length in cells, enabling cancer cells to proliferate indefinitely. Nevertheless, the specific mechanism of telomerase activation in non-small cell lung cancer (NSCLC) remains unclear, and post-transcriptional regulation of hTERT could be a potential activation mechanism.

MATERIALS AND METHODS

We explored the regulatory impact of CMSS1 on hTERT expression in NSCLC cells using several methods: Yeast three-hybrid system, Reporter gene assay, Western blot, RNA decay assay, and Telomere length measurement. Our analysis revealed significant overexpression of CMSS1 in NSCLC, which correlated with poor prognosis, as determined by bioinformatics and tissue microarray techniques. RNA sequencing analysis showed that CMSS1 knockdown influenced the adhesion capabilities of NSCLC cells. Additionally, potential interacting proteins with CMSS1 were identified through mass spectrometry and co-immunoprecipitation experiments.

KEY FINDINGS

We discovered that CMSS1 regulates hTERT expression in NSCLC cells by binding to the 5' UTR of hTERT mRNA, impacting its mRNA stability and thereby influencing NSCLC progression. RNA-Seq results and adhesion experiments indicated that CMSS1 knockdown disrupts cell adhesion. hTERT also affects cell adhesion in NSCLC, underscoring CMSS1's role as an upstream regulator of hTERT. Mass spectrometry and Co-IP studies suggest potential interactions between CMSS1, RBM34, and DDX5 that further modulate hTERT expression.

SIGNIFICANCE

These findings indicate that CMSS1 plays a crucial role in NSCLC progression through its interaction with hTERT, making it a promising therapeutic target.