The Hippo effector TAZ promotes cancer stemness by transcriptional activation of SOX2 in head neck squamous cell carcinoma

Abstract

The Hippo-TAZ signaling has emerged as a fundamental regulator underlying cancer stem cells (CSCs) stemness which intricately associates with local recurrence and metastatic spreading in head neck squamous cell carcinoma (HNSCC). However, the precise downstream targets of TAZ responsible for HNSCC CSCs maintenance remain largely underexplored. Here, we identified Sex determining region Y box 2 (SOX2) as a putative downstream target of TAZ to promote CSCs maintenance and tumorigenicity in HNSCC. Both TAZ and SOX2 were significantly enriched in CSCs subpopulation (CD44 + CD133 + ) isolated from Cal27 and Fadu cells via fluorescence-activated cell sorting. TAZ knockdown significantly reduced expression of SOX2 at both mRNA and protein levels, whereas its ectopic overexpression markedly increased its abundance in HNSCC cells. Moreover, reintroduction of ectopic SOX2 abolished, at least in part, the reduced tumorsphere formation and tumorigenicity in vivo induced by TAZ knockdown. Mechanistically, transcriptional complex formed by TAZ and TEAD4 was recruited to two binding sites in SOX2 promoter, which in turn facilitated transcription of SOX2 in HNSCC cells. In addition, the abundance of TAZ and SOX2 was positively correlated in HNSCC clinical samples, and both upregulations of TAZ and SOX2 associated with the worst survival. Taken together, our data reveal a previously unknown mechanistic linkage between TAZ and SOX2 and identify SOX2 as a direct downstream target of TAZ in modulating CSCs self-renewal and maintenance in HNSCC. These findings suggest that targeting TAZ-SOX2 axis might be a promising therapeutic strategy for HNSCC.

<p>Structural and Functional Overview of TEAD4 in Cancer Biology</p>

“…63 The TEAD4-TAZ complex can also bind to the promoter of SOX2 and modulate cancer stem cell selfrenewal in head-neck squamous cell carcinoma. 38 Consistent with the findings above, TEAD4-induced metastasis is common in gastric cancer, 36 breast cancer, 48 lung cancer, 42 and colorectal cancer. 11 This is plausible as cancer cells that undergo EMT detach, traverse the basement membrane, enter the bloodstream, and disseminate elsewhere for metastatic colonization.…”

Genome-wide CRISPR screens of oral squamous cell carcinoma reveal fitness genes in the Hippo pathway

“…Further, the activation of the PI3K through mitogenic signaling inhibits the Hippo pathway leading to YAP1 activation and cell growth ( Fan et al, 2013 ). On the other hand, WWTR1 was shown to act upstream of SOX2, facilitating stemnesses in HNSCC ( Li et al, 2019 ). Intriguingly, while WWTR1 knockdown led to reduction of SOX2 mRNA and protein expression, this was not seen when YAP1 was knockdown in the HNSCC cells (Cal27 and Fadu) ( Li et al, 2019 ; Huang et al, 2017 ).…”

“…On the other hand, WWTR1 was shown to act upstream of SOX2, facilitating stemnesses in HNSCC ( Li et al, 2019 ). Intriguingly, while WWTR1 knockdown led to reduction of SOX2 mRNA and protein expression, this was not seen when YAP1 was knockdown in the HNSCC cells (Cal27 and Fadu) ( Li et al, 2019 ; Huang et al, 2017 ). In support of that, an inverse relationship between the expression levels of YAP1 and ΔNp63 were reported in lung SCC tumor samples ( Huang et al, 2017 ).…”

Characterisation of a subpopulation of CD133+ cancer stem cells from Chinese patients with oral squamous cell carcinoma

“…In the present study, we characterised for the first time CSCs in populations of primary OSCC cells using CD133. Other studies suggest that SOX2 is critically involved, at least in part, in cancer initiation and progression via modulation of CSC stemness 39 . Moreover, a review indicated that NANOG, ALDH1A1, and OCT4 could serve as CSC markers and were predictive of poor prognosis 40 .…”