The Hippo pathway oncoprotein YAP promotes melanoma cell invasion and spontaneous metastasis

Zhang, Xiaomeng; Yang, Lie; Szeto, Pacman; Abali, Gamze Kuser; Zhang, Youfang; Kulkarni, Aishwarya; Amarasinghe, Kaushalya; Li, Jason; Vergara, Ismael A.; Molania, Ramyar; Papenfuss, Anthony T.; McLean, Catriona; Shackleton, Mark; Harvey, Ken

doi:10.1038/s41388-020-1362-9

Cited by 66 publications

(88 citation statements)

References 64 publications

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“…This suggests that YAP activity can compensate for loss of BRAF V600E signaling. Given MAPK inhibitor resistance remains a significant component of treatment failure, our data suggests that co-targeting MAPK and YAP-TEAD signaling could simultaneously prevent resistance (69) and decrease melanoma cell viability (32,77).…”

Section: ! Discussionmentioning

confidence: 99%

“…It is not known if Hippo pathway activation contributes to the growth arrest of nevus melanocytes. Moreover, while Hippo pathway inactivation has been suggested to promote cutaneous melanoma growth and invasion (30)(31)(32), it remains unknown whether Hippo inactivation is sufficient to induce cutaneous melanoma initiation and/or progression. Here, we use a combination of in vitro and in vivo model systems to examine the role of the Hippo tumor suppressor pathway in restraining melanoma development.…”

Section: Introductionmentioning

confidence: 99%

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Inactivation of the Hippo Tumor Suppressor Pathway Promotes Melanoma

Kingston

Xia

et al. 2021

Preprint

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Human melanomas are commonly driven by activating mutations in BRAF, which promote melanocyte proliferation through constitutive stimulation of the MAPK pathway. However, oncogenic BRAF alone is insufficient to promote melanoma; instead, its expression merely induces a transient burst of proliferation that ultimately ceases with the development of benign nevi (i.e. moles) comprised of growth-arrested melanocytes. The tumor suppressive mechanisms that induce this melanocytic growth arrest remain poorly understood. Recent modeling studies have suggested that the growth arrest of nevus melanocytes is not solely due to oncogene activation in individual cells, but rather due to cells sensing and responding to their collective overgrowth, similar to what occurs in normal tissues. This cell growth arrest is reminiscent of the arrest induced by activation of the Hippo tumor suppressor pathway, which is an evolutionarily conserved pathway known to regulate organ size. Herein, we demonstrate that oncogenic BRAF signaling activates the Hippo pathway in vitro, which leads to inhibition of the pro-growth transcriptional co-activators YAP and TAZ, ultimately promoting the growth arrest of melanocytes. We also provide evidence that the Hippo tumor suppressor pathway is activated in growth-arrested nevus melanocytes in vivo, both from single-cell sequencing of mouse models of nevogenesis and human tissue samples. Mechanistically, we observe that oncogenic BRAF promotes both ERK-dependent alterations in the actin cytoskeleton and whole-genome-doubling events, and that these two effects independently promote Hippo pathway activation. Lastly, we demonstrate that abrogation of the Hippo pathway, via melanocyte-specific deletion of the Hippo kinases Lats1/2, enables oncogenic BRAF-expressing melanocytes to bypass nevus formation, thus leading to the rapid onset of melanoma with 100% penetrance. This model is clinically relevant, as co-heterozygous loss of LATS1/2 is observed in ∼15% of human melanomas. Collectively, our data reveal that the Hippo pathway enforces the stable growth arrest of nevus melanocytes and therefore represents a critical and previously unappreciated barrier to melanoma development.

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Section: ! Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Inactivation of the Hippo Tumor Suppressor Pathway Promotes Melanoma

Kingston

Xia

et al. 2021

Preprint

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“…Spontaneous metastasis status in in vivo models was evaluated by human mitochondrial IHC of liver, lung and lymph nodes 50 . Briefly, slides were de-waxed and antigen retrieval was performed in a pressure cooker at 125°C for 3 min employing an Antigen Retrieval solution (Dako, pH6 for EZH2, pH9 for Anti-human Mitochondrial Antibody).…”

Section: Methodsmentioning

confidence: 99%

EZH2 Abundance Regulated by UHRF1/UBE2L6/UBR4 Ubiquitin System is the Potential Therapeutic Target to Trigger Pigmented Phenotype in Melanoma

Zhang

Szeto

et al. 2021

Preprint

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Cellular heterogeneity in cancer is linked to disease progression and therapy response, although the mechanisms regulating distinct cellular states within tumours are not well understood. To address this, we identified melanin pigment content as a major source of phenotypic and functional heterogeneity in melanoma and compared RNAseq data from high (HPC) and low pigmented melanoma cells (LPC), revealing the polycomb repressor complex protein, EZH2, as a master regulator of these states. EZH2 protein, but not RNA expression, was found to be upregulated in LPCs and inversely correlated with melanin in pigmented patient melanomas. Surprisingly, conventional EZH2 methyltransferase inhibitors, GSK126 and EPZ6438, had no effect on LPC survival, clonogenicity and pigmentation, despite fully inhibiting methyltransferase activity. In contrast, EZH2 silencing by siRNA strategy or DZNep, MS1943 that reduces EZH2 protein levels, significantly inhibited cell growth in LPCs by hampering ribosome biogenesis. In addition, decline in EZH2 protein level induces pigmented cell phenotype by inducing melanin biosynthesis. Proteasomal inhibitor, MG132 treatment induced EZH2 protein levels in HPCs prompted us to look for differentially regulated ubiquitin system proteins in HPC vs LPCs. UBE2L6, E2 conjugating enzyme has been shown to be downregulated significantly in LPCs by UHRF1-mediated CpG methylation. Both biochemical assays and animal studies demonstrated that UBE2L6 expression decline, in turn, promotes EZH2 protein stability due to lack of ubiquitination on K381 residue in LPCs. UBR4 cooperates with UBE2L6 to facilitate this ubiquitination process. Targeting UHRF1/UBE2L6/UBR4 axis can be a better treatment option to trigger HPC state in melanoma in which conventional EZH2 inhibitors are ineffective.

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“…In YAP1-transformed MIHA HCC cells, the knockdown of Axl interfered with migration and invasion and reduced the metastatic potential of the cells [16]. Another study done using melanoma cancer cell lines showed that Axl is an important gene in YAP-induced melanoma cell invasion [45].…”

Section: Invasion and Migrationmentioning

confidence: 97%

The Role of the Receptor Tyrosine Kinase Axl in Carcinogenesis and Development of Therapeutic Resistance: An Overview of Molecular Mechanisms and Future Applications

Wium

Ajayi-Smith

Paccez

et al. 2021

Cancers

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Resistance to chemotherapeutic agents by cancer cells has remained a major obstacle in the successful treatment of various cancers. Numerous factors such as DNA damage repair, cell death inhibition, epithelial–mesenchymal transition, and evasion of apoptosis have all been implicated in the promotion of chemoresistance. The receptor tyrosine kinase Axl, a member of the TAM family (which includes TYRO3 and MER), plays an important role in the regulation of cellular processes such as proliferation, motility, survival, and immunologic response. The overexpression of Axl is reported in several solid and hematological malignancies, including non-small cell lung, prostate, breast, liver and gastric cancers, and acute myeloid leukaemia. The overexpression of Axl is associated with poor prognosis and the development of resistance to therapy. Reports show that Axl overexpression confers drug resistance in lung cancer and advances the emergence of tolerant cells. Axl is, therefore, an important candidate as a prognostic biomarker and target for anticancer therapies. In this review, we discuss the consequence of Axl upregulation in cancers, provide evidence for its role in cancer progression and the development of drug resistance. We will also discuss the therapeutic potential of Axl in the treatment of cancer.

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The Hippo pathway oncoprotein YAP promotes melanoma cell invasion and spontaneous metastasis

Cited by 66 publications

References 64 publications

Inactivation of the Hippo Tumor Suppressor Pathway Promotes Melanoma

Inactivation of the Hippo Tumor Suppressor Pathway Promotes Melanoma

EZH2 Abundance Regulated by UHRF1/UBE2L6/UBR4 Ubiquitin System is the Potential Therapeutic Target to Trigger Pigmented Phenotype in Melanoma

The Role of the Receptor Tyrosine Kinase Axl in Carcinogenesis and Development of Therapeutic Resistance: An Overview of Molecular Mechanisms and Future Applications

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