Mammalian Hippo kinase pathway is downregulated by BCL-2 via protein degradation

Won, Gun Woo; Park, Seon Hee; Park, Joonwoo; Lee, Young‐Joo; Lee, Yong Hee

doi:10.1016/j.bbrc.2019.03.015

Cited by 11 publications

(6 citation statements)

References 23 publications

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“…We also showed that Bcl-2 regulates MST2 protein stability. Our results are consistent with published data demonstrating that Bcl-2 inhibits protein levels of MST2 in human embryonic kidney cells by inducing proteasomal degradation, and that inhibition of Bcl-2 restores the level of MST2 kinase, resulting in increased cell death [ 65 ]. Also, a recent study described a link between Bcl-2 and YAP [ 66 ], demonstrating that TEAD4 binds to the promoter regions of Bcl-2 and that YAP silencing abrogated downregulated Bcl-2 protein in colorectal cancer cells [ 66 ].…”

Section: Discussionsupporting

confidence: 93%

Bcl-2 dependent modulation of Hippo pathway in cancer cells

D’Aguanno,

Brignone,

Scalera

et al. 2024

Cell Commun Signal

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Introduction Bcl-2 and Bcl-xL are the most studied anti-apoptotic members of Bcl-2 family proteins. We previously characterized both of them, not only for their role in regulating apoptosis and resistance to therapy in cancer cells, but also for their non-canonical functions, mainly including promotion of cancer progression, metastatization, angiogenesis, and involvement in the crosstalk among cancer cells and components of the tumor microenvironment. Our goal was to identify transcriptional signature and novel cellular pathways specifically modulated by Bcl-2. Methods We performed RNAseq analysis of siRNA-mediated transient knockdown of Bcl-2 or Bcl-xL in human melanoma cells and gene ontology analysis to identify a specific Bcl-2 transcriptional signature. Expression of genes modulated by Bcl-2 and associated to Hippo pathway were validated in human melanoma, breast adenocarcinoma and non-small cell lung cancer cell lines by qRT-PCR. Western blotting analysis were performed to analyse protein expression of upstream regulators of YAP and in relation to different level of Bcl-2 protein. The effects of YAP silencing in Bcl-2 overexpressing cancer cells were evaluated in migration and cell viability assays in relation to different stiffness conditions. In vitro wound healing assays and co-cultures were used to evaluate cancer-specific Bcl-2 ability to activate fibroblasts. Results We demonstrated the Bcl-2-dependent modulation of Hippo Pathway in cancer cell lines from different tumor types by acting on upstream YAP regulators. YAP inhibition abolished the ability of Bcl-2 to increase tumor cell migration and proliferation on high stiffness condition of culture, to stimulate in vitro fibroblasts migration and to induce fibroblasts activation. Conclusions We discovered that Bcl-2 regulates the Hippo pathway in different tumor types, promoting cell migration, adaptation to higher stiffness culture condition and fibroblast activation. Our data indicate that Bcl-2 inhibitors should be further investigated to counteract cancer-promoting mechanisms.

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Section: Discussionsupporting

confidence: 93%

Bcl-2 dependent modulation of Hippo pathway in cancer cells

D’Aguanno,

Brignone,

Scalera

et al. 2024

Cell Commun Signal

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“…Recent cancer-related studies have determined that certain proteins ( e.g. , BCL-2, P4HA2) interact with SAV1, leading to its ubiquitination and proteasomal degradation 32 , 33 . However, the regulatory molecules for SAV1 in RA FLSs remain unknown.…”

Section: Discussionmentioning

confidence: 99%

GRK2 mediated degradation of SAV1 initiates hyperplasia of fibroblast-like synoviocytes in rheumatoid arthritis

Guo,

Jiang,

Chu

et al. 2024

Acta Pharmaceutica Sinica B

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“…Another reason could be the highly complex epigenetic and post-transcriptional regulation of SAV1 gene expression, which could also explain the differences in mRNA and protein expression levels. Won et al [30] discovered that an anti-apoptotic protein BCL-2 could stimulate the proteasomal degradation of the SAV1 protein through direct binding to SAV1 and that BCL-2 overexpression did not lead to a reduction in SAV1 mRNA levels, indicating that this phenomenon occurs at a post-transcriptional level. Moreover, they demonstrated in MCF7 (human breast adenocarcinoma) cells high levels of the SAV1 protein but low levels of the BCL-2 protein.…”

Section: Discussionmentioning

confidence: 99%

Impaired Expression of the Salvador Homolog-1 Gene Is Associated with the Development and Progression of Colorectal Cancer

Kowalczyk,

Krazinski,

Piotrowska

et al. 2023

Cancers

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Salvador homolog-1 (SAV1) is a component of the Hippo pathway that regulates tissue growth and homeostasis by affecting diverse cell processes, including apoptosis, cell division, and differentiation. The aberrant expression of Hippo pathway components has been observed in various human cancers. This study aimed to examine the expression level of the SAV1 gene in colorectal cancer (CRC) and its prognostic value and associations with tumor progression. We obtained matched pairs of tumor tissue and non-cancerous mucosa of the large intestine from 94 CRC patients as well as 40 colon biopsies of healthy subjects collected during screening colonoscopy. The tissue samples and CRC cell lines were quantified for SAV1 mRNA levels using the quantitative polymerase chain reaction method, while SAV1 protein expression was estimated in the paired tissues of CRC patients using immunohistochemistry. The average level of SAV1 mRNA was decreased in 93.6% of the tumor tissues compared to the corresponding non-cancerous tissues and biopsies of healthy colon mucosa. A downregulated expression of SAV1 mRNA was also noted in the CRC cell lines. Although the average SAV1 immunoreactivity was increased in the CRC samples compared to the non-cancerous tissues, a decreased immunoreactivity of the SAV1 protein in the tumor specimens was associated with lymph node involvement and higher TNM disease stage and histological grade. The results of our study suggest that the impaired expression of SAV1 is involved in CRC progression.

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Mammalian Hippo kinase pathway is downregulated by BCL-2 via protein degradation

Cited by 11 publications

References 23 publications

Bcl-2 dependent modulation of Hippo pathway in cancer cells

Bcl-2 dependent modulation of Hippo pathway in cancer cells

GRK2 mediated degradation of SAV1 initiates hyperplasia of fibroblast-like synoviocytes in rheumatoid arthritis

Impaired Expression of the Salvador Homolog-1 Gene Is Associated with the Development and Progression of Colorectal Cancer

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