YAP1 Regulates OCT4 Activity and SOX2 Expression to Facilitate Self-Renewal and Vascular Mimicry of Stem-Like Cells

Abstract

Non-small cell lung cancer (NSCLC) is highly correlated with smoking and has very low survival rates. Multiple studies have shown that stem-like cells contribute to the genesis and progression of NSCLC. Our results show that the transcriptional co-activator YAP1, which is the oncogenic component of the Hippo signaling pathway, is elevated in the stem-like cells from NSCLC and contributes to their self-renewal and ability to form angiogenic tubules. Inhibition of YAP1 by a small molecule or depletion of YAP1 by siRNAs suppressed self-renewal and vascular mimicry of stem-like cells. These effects of YAP1 were mediated through the embryonic stem cell transcription factor, Sox2. YAP1 could transcriptionally induce Sox2 through a physical interaction with Oct4; Sox2 induction occurred independent of TEAD2 transcription factor, which is the predominant mediator of YAP1 functions. The binding of Oct4 to YAP1 could be detected in cell lines as well as tumor tissues; the interaction was elevated in NSCLC samples compared to normal tissue as seen by proximity ligation assays. YAP1 bound to Oct4 through the WW domain, and a peptide corresponding to this region could disrupt the interaction. Delivery of the WW domain peptide to stem-like cells disrupted the interaction and abrogated Sox2 expression, self-renewal and vascular mimicry. Depleting YAP1 reduced the expression of multiple EMT genes and prevented the growth and metastasis of tumor xenografts in mice; overexpression of Sox2 in YAP1 null cells rescued these functions. These results demonstrate a novel regulation of stem-like functions by YAP1, through the modulation of Sox2 expression.

The Hippo pathway in colorectal cancer

“…The most commonly focused gene, YAP1, was found to be involved in tumour development and progression in different malignancies, including CRC. Although increased level of the YAP1 protein (assessed by WB) was found in most studies [83,[88][89][90][91] suggesting its oncogenic role, the under-expression was also observed in breast [92] and colorectal cancer [79]. The study of Barry et al showed decreased expression of YAP1 in high grade tumours and stage IV [79].…”

“…Mouse KO: various cancer types developed [141] TSG: downregulation in CRC [142] TAZ Mutations in Barth syndrome [143] OG: overexpression in breast cancer [144], HCC [145] OG: overexpression in CRC [85] YAP1 OG: overexpression in NSCLC [88], prostate [90], breast [91], gallbladder cancer [146] and glioma [89] TSG: decreased expression in breast cancer [92] OG: overexpression in CRC [83], in CRC cases resistant to cetuximab [102] TSG: underexpression in CRC [79] AML -acute myeloid leukaemia; CCL -cancer cell line(s); HCC -hepatocellular carcinoma; KO -knock out; LOH -loss of heterozygosity; NSCLC -non-small cell lung cancer; OG -oncogene; TSG -tumour suppressor gene epinephrine or glucagon repress YAP1/TAZ activity [45,46]. YAP1 could also be regulated by matrix stiffness independently from LATS1/2 phosphorylation.…”

Overexpression of the YAP1 oncogene in clear cell renal cell carcinoma is associated with poor outcome

“…Its deregulation is frequently observed in many types of malignancies, suggesting that alterations of this signaling are connected with cancer progression and patient survival (7)(8)(9)21,33,34). The core components of this pathway include MST1/2, SAV1, LATS1/2 and MOB1 proteins (10,12,15).…”

“…Decreased expression of LATS1 gene and protein was observed in breast (16), colorectal (17) and non-small cell lung cancers (18), whereas lower MST2 mRNA and protein levels were reported in hepatocellular carcinoma (19) and malignant mesothelioma (20). Furthermore, the overexpression of YAP1 protein was observed in many cancer types, including lung (21), prostate (22), breast (23), and gallbladder cancers (24) and glioma (25). Since to date no quantitative analyses of the expression of the Hippo pathway effector, YAP1, and its key components, MST2 and LATS1 kinases, have been assessed in ccRCC, we decided to compare their mRNA and protein levels in tumor and normal kidney tissues, and in metastases of ccRCC.…”

Tobacco nitrosamine NNK increases ALDH-positive cells via ROS-Wnt signaling pathway in A549 human lung cancer cells

“…We and other groups have demonstrated that A549 cells can be used to identify signaling molecules which acquire lung CSCs by an Aldefluor assay (Hirata et al, 2014;Bora-Singhal et al, 2015;Oh et al, 2015). To examine the effect of NNK on the size of the lung CSCs, we performed an Aldefluor assay in human lung cancer cell line A549.…”