Promoter hypermethylation-mediated down-regulation of LATS1 and LATS2 in human astrocytoma

Jiang, Zheng; Li, Xingang; Hu, Jin; Zhou, Wei; Jiang, Yuquan; Li, Gang; Lu, Daru

doi:10.1016/j.neures.2006.09.006

Cited by 140 publications

(128 citation statements)

References 27 publications

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“…In addition, we previously found that inactivation of LATS1 caused cytokinesis defects, genetic instability, and polyploidy, all of which are hallmarks of cancer (8). Moreover, reduced expression and promoter methylation of LATS1 are also found in various cancers, including leukemia, breast cancer, astrocytoma, and softtissue sarcoma (9)(10)(11). Given such critical role in cancer, studies of LATS1 may therefore greatly facilitate our understanding of the molecular mechanism that leads to tumorigenesis.…”

Section: T7-r1(d505v)-yfp 35s:plc2-cfpmentioning

confidence: 99%

Itch E3 ubiquitin ligase regulates large tumor suppressor 1 stability

Zhou

She

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

112

109

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The large tumor suppressor 1 (LATS1) is a serine/threonine kinase and tumor suppressor found down-regulated in a broad spectrum of human cancers. LATS1 is a central player of the emerging Hippo-LATS suppressor pathway, which plays important roles in cell proliferation, apoptosis, and stem cell differentiation. Despite the ample data supporting a role for LATS1 in tumor suppression, how LATS1 is regulated at the molecular level remains largely unknown. In this study, we have identified Itch, a HECT class E3 ubiquitin ligase, as a unique binding partner of LATS1. Itch can complex with LATS1 both in vitro and in vivo through the PPxY motifs of LATS1 and the WW domains of Itch. Significantly, we found that overexpression of Itch promoted LATS1 degradation by polyubiquitination through the 26S proteasome pathway. On the other hand, knockdown of endogenous Itch by shRNAs provoked stabilization of endogenous LATS1 proteins. Finally, through several functional assays, we also revealed that change of Itch abundance alone is sufficient for altering LATS1-mediated downstream signaling, negative regulation of cell proliferation, and induction of apoptosis. Taking these data together, our study identifies E3 ubiquitin ligase Itch as a unique negative regulator of LATS1 and presents a possibility of targeting LATS1/Itch interaction as a therapeutic strategy in cancer.

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Section: T7-r1(d505v)-yfp 35s:plc2-cfpmentioning

confidence: 99%

Itch E3 ubiquitin ligase regulates large tumor suppressor 1 stability

Zhou

She

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

112

109

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“…Similar to YAP overexpression, ablation of the Hippo pathway components Mer and Sav and double knockout of Mst1/2 in mice result in liver enlargement and tumor formation characteristic of HCC and cholangiocarcinoma (CC) (Zhou et al, 2009;Benhamouche et al, 2010;Lee et al, 2010;Lu et al, 2010;Song et al, 2010;. Aberrant Mst1/2 and Lats1/2 expression is observed in human cancers (Hisaoka et al, 2002;Jimé-nez-Velasco et al, 2005;Takahashi et al, 2005;Jiang et al, 2006;Minoo et al, 2007;Seidel et al, 2007;Cho et al, 2009;Zhou et al, 2009). Lats2 is also found mutated in human mesothelioma cell lines and non-small cell lung cancer (Strazisar et al, 2009;Murakami et al, 2011).…”

Section: The Mammalian Hippo Pathwaymentioning

confidence: 99%

The Hippo pathway regulates stem cell proliferation, self-renewal, and differentiation

et al. 2012

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This pathway was first found to inhibit cell proliferation and promote apoptosis, therefore regulating cell number and organ size in both Drosophila and mammals. However, in several organs, disturbance of the pathway leads to specific expansion of the progenitor cell compartment and manipulation of the pathway in embryonic stem cells strongly affects their self-renewal and differentiation. In this review, we summarize current observations on roles of the Hippo pathway in different types of stem cells and discuss how these findings changed our view on the Hippo pathway in organ development and tumorigenesis.

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“…44,45 A tumor suppressive role for Lats1/2 is suggested by observations of hypermethylation of Lats1/2 promoters and mRNA downregulation in human soft tissue sarcoma, astrocytoma and breast cancer. [46][47][48] In addition, allelic loss of Lats1 has been reported in ovarian cancer. 49 In vitro, overexpression of Lats1 or Lats2 is sufficient to suppress ephithelial-messenchymal transition and tumor growth of cancer cells while their downregulation result in cell overgrowth and transformation.…”

Section: Mst1/2mentioning

confidence: 99%