LATS (large tumor suppressor) or warts is a Ser/Thr kinase that belongs to the Ndr/LATS subfamily of AGC (protein kinase A/PKG/PKC) kinases. It is a tumor suppressor gene originally isolated from Drosophila and recently isolated from mice and humans. Drosophila or mice mutant for LATS develop tumors in various tissues. Recent studies in Drosophila demonstrate that LATS is a central player of an emerging tumor suppressor pathway called the Hippo-LATS/Warts pathway that suppresses tumor growth by regulating cell proliferation, cell growth, and cell death. Although tremendous progress has been made toward understanding the roles of LATS in tumorigenesis, the kinase substrates of LATS or downstream target proteins mediating LATS function remain largely unknown. In this study, we have provided convincing evidence that the LATS1 tumor suppressor can bind to and phosphorylate transcription regulator and oncogene YAP in vitro and in vivo. We have also identified HX(R/H/K)XX(S/T) as the consensus phosphorylation sequence for LATS/Ndr kinase substrates. Significantly, we have discovered that LATS1 inactivates YAP oncogenic function by suppressing its transcription regulation of cellular genes via sequestration of YAP in the cytoplasm after phosphorylation of YAP. Finally, by using microarray analysis, we have also identified many oncogenes or tumor suppressor genes up-regulated or down-regulated by YAP. These research findings will have profound impacts on our understanding of the molecular mechanism of the LATS tumor suppressor and the emerging Hippo-LATS/Warts pathway.
Taxol (paclitaxel) resistance represents a major challenge in breast cancer treatment. The TAZ (transcriptional co-activator with PDZ-binding motif) oncogene is a major component of the novel Hippo-LATS signaling pathway and a transcriptional coactivator that interacts with and activates multiple transcription factors to regulate various biological processes. Here, we report that elevated levels of TAZ found in human breast cancer cells are responsible for their resistance to Taxol. DNA microarray analysis identified the oncogenes Cyr61 and CTGF as downstream transcriptional targets of TAZ. Short hairpin RNA-mediated knockdown of both Cyr61 and CTGF reversed TAZ-induced Taxol resistance in breast cancer cells. Interaction of TAZ with the TEAD family of transcription factors was essential for TAZ to activate the Cyr61/CTGF promoters and to induce Taxol resistance. Our findings define the TAZ-TEAD-Cyr61/CTGF signaling pathway as an important modifier of the Taxol response in breast cancer cells, as well as highlighting it as a novel therapeutic target to treat drug-resistant breast cancers that arise commonly at advanced stages of disease. Cancer Res; 71(7); 2728-38. Ó2011 AACR.
Cutaneous melanoma is an aggressive form of human skin cancer characterized by high metastatic potential and poor prognosis. To better understand the role of microRNAs (miRNAs) in melanoma, the expression of 470 miRNAs was profiled in tissue samples from benign nevi and metastatic melanomas. We identified 31 miRNAs that were differentially expressed (13 upregulated and 18 down-regulated) in metastatic melanomas relative to benign nevi. Notably Cutaneous melanoma is a form of skin cancer characterized by aggressive metastatic growth and poor prognosis. 1 The incidence of melanoma continues to increase in many parts of the world.2 The median survival time of patients with metastatic melanoma is 6 months, and the 5-year survival rate is less than 5%.3 Genetic factors and exposure to ultraviolet radiation are risk factors for melanoma pathogenesis.4
The Hippo pathway component WW domain-containing transcription regulator 1 (TAZ) is a transcriptional coactivator and an oncogene in breast and lung cancer. Transcriptional targets of TAZ that modulate immune cell function in the tumor microenvironment are poorly understood. Here, we perform a comprehensive screen for immune-related genes regulated by TAZ and its paralog YAP using NanoString gene expression profiling. We identify the immune checkpoint molecule as a target of Hippo signaling. The upstream kinases of the Hippo pathway, mammalian STE20-like kinase 1 and 2 (MST1/2), and large tumor suppressor 1 and 2 (LATS1/2), suppress PD-L1 expression while TAZ and YAP enhance PD-L1 levels in breast and lung cancer cell lines. PD-L1 expression in cancer cell lines is determined by TAZ activity and TAZ/YAP/TEAD increase promoter activity. Critically, TAZ-induced PD-L1 upregulation in human cancer cells is sufficient to inhibit T-cell function. The relationship between TAZ and PD-L1 is not conserved in multiple mouse cell lines, likely due to differences between the human and mouse promoters. To explore the extent of divergence in TAZ immune-related targets between human and mouse cells, we performed a second NanoString screen using mouse cell lines. We show that many targets of TAZ may be differentially regulated between these species. These findings highlight the role of Hippo signaling in modifying human/murine physiologic/pathologic immune responses and provide evidence implicating TAZ in human cancer immune evasion. Human-specific activation of PD-L1 by a novel Hippo signaling pathway in cancer immune evasion may have a significant impact on research in immunotherapy. .
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