GTSE1 promotes esophageal squamous cell carcinoma stemness via the Hippo signaling pathway

Cancer stem cells (CSCs) are pivotal in driving tumorigenesis, metastasis, and resistance to multiple drugs. In this study, genes associated with stemness were identified, and the effects of GTSE1 on esophageal squamous cell carcinoma (ESCC) stemness and its underlying mechanism were elucidated.

We utilized a trained stemness index model, adapted from a one-class logistic regression (OCLR) machine-learning approach, to evaluate the stemness indices of ESCC samples based on gene expression-based stemness index (mRNAsi). Subsequent algorithmic and single-cell subtype analyses confirmed the predictive capability of the mRNAsi and pinpointed GTSE1 as a potential target. Loss-of-function and gain-of-function genetic experiments were conducted to evaluate the influence of GTSE1 on ESCC self-renewal and tumor progression. Mechanistic investigations involved RNA sequencing (RNA-seq), immunofluorescence, coimmunoprecipitation (Co-IP) and so on. Additionally, the efficacy of verteporfin (a Hippo pathway inhibitor) was evaluated in vitro and vivo.

The analysis of the mRNAsi in bulk RNA-seq and single RNA-seq data reveals elevated expression of GTSE1 in the high mRNAsi subgroup and clusters of highly malignant single cells. Functional studies demonstrate that the depletion of GTSE1 hinders self-renewal and progression of ESCC. Mechanistically, GTSE1 modulates the Hippo signaling pathway. GTSE1 regulates cytoskeletal tension and interacts with LATS1 to facilitate its ubiquitination and degradation, thereby reducing YAP phosphorylation and promoting its nuclear translocation. Treatment with verteporfin, significantly impairs self-renewal and progression, particularly in cells with high GTSE1 expression.

This study underscores the association of GTSE1 with the stemness of ESCC, highlighting its interaction with LATS1 to regulate nuclear localization of YAP and modulate the Hippo signaling pathway. Consequently, GTSE1 emerges as a promising therapeutic target for ESCC.