LATS1/2 kinases trigger self-renewal of cancer stem cells in aggressive oral cancer

Abstract

Cancer stem cells (CSCs), which play important roles in tumor initiation and progression, are resistant to many types of therapies. However, the regulatory mechanisms underlying CSC-specific properties, including self-renewal, are poorly understood. Here, we found that LATS1/2, the core Hippo pathway-kinases, were highly expressed in the oral squamous cell carcinoma line SAS, which exhibits high capacity of CSCs, and that depletion of these kinases prevented SAS cells from forming spheres under serum-free conditions. Detailed examination of the expression and activation of LATS kinases and related proteins over a time course of sphere formation revealed that LATS1/2 were more highly expressed and markedly activated before initiation of self-renewal. Moreover, TAZ, SNAIL, CHK1/2, and Aurora-A were expressed in hierarchical, oscillating patterns during sphere formation, suggesting that the process consists of four sequential steps. Our results indicate that LATS1/2 trigger self-renewal of CSCs by regulating the Hippo pathway, the EMT, and cell division.

Outcome in serous ovarian cancer is not associated with LATS expression

“…Likewise, LATS1 and LATS2 expression was comparable among epithelial, intermediate, and mesenchymal ovarian cancer cell lines, indicating that LATS protein expression was not associated with the cells’ EMT status. This is at odds with the view that LATS expression declines when cells transition from epithelial to mesenchymal (Nozaki et al 2019; Moroishi et al 2015; Lei et al 2008). Opposed to these studies is a report showing that LATS can potentiate tumor-promoting factors and augment EMT (Zhang et al 2012).…”

“…To validate these previous data, we investigated LATS expression (1) and clinical outcome in ovarian cancer using various publicly accessible transcriptomic data sets and (2) in our Swiss ovarian cancer patient cohort and related the results to various clinicopathological parameters. As LATS expression has also been shown to regulate epithelial-mesenchymal transition (EMT), a cellular program that promotes invasion and metastasis during cancer development, and modulate drug responses (Nozaki et al 2019; Zhang et al 2012; Takahashi et al 2007; Kawahara et al 2008), we determined LATS protein expression in a panel of ovarian cancer cell lines and investigated (3) whether LATS expression in these cell lines was an indicator for the EMT state of the cells and for the sensitivity to chemotherapeutic drugs.…”

EZH2 activates CHK1 signaling to promote ovarian cancer chemoresistance by maintaining the properties of cancer stem cells

“…The relevance of our findings is further supported by a research study demonstrating that CHK1 inhibitors in combination with chemotherapy dramatically reduced CSC survival in vitro by inducing premature cell cycle progression and mitotic catastrophe in non-small cell lung cancer 46 . Additionally, another study proved that knockdown of CHK1 successfully inhibited sphere formation of CSCs in the absence of cisplatin in aggressive oral cancer 47 . Consistently, we found that upregulation of CHK1 can increase the sphere formation capacity of ovarian CSCs without cisplatin treatment ( Figure 5 B ), which may be due to the reduction of DNA damage caused by other external factors.…”

Targeting the Hippo Pathway in Prostate Cancer: What’s New?

“…Cancer stem cells are important in driving therapy resistance and transcription factors associated with pluripotency, specifically Nanog, Oct4 and Sox2, have been associated with aggressive PC [108]. In other cancers, deletion of LATS and the resultant up-regulation in YAP/TAZ activity resulted in uncontrolled expansion of Sox2-positive cells [109], whilst LATS1/2 activity can trigger self-renewal of cancer stem cells in aggressive oral cancer [110]. Therefore, it would be interesting to investigate the levels of Hippo pathway activity in this subgroup of patients with high expression of Oct 4, Sox2 and Nanog.…”