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YAP modulates mitochondrial function and sensitive to NAMPT inhibition in triple negative breast cancer cells

ABSTRACT: YAP and TAZ coordinate several NAD+-dependent processes like glycolysis, fatty acid oxidation and glutaminolysis in nutrient-deprivation conditions. However, correlations between NAD(H) levels and YAP/TAZ metabolic function are still poorly understood. We showed that stable silencing of YAP in the triple-negative breast cancer (TNBC) cell line MDAMB231 (MDA shYAP) rescued the toxicity of the NAD+ depletion agent FK866, both in 2D and in 3D culturing, prevented ROS accumulation and apoptosis. As MDA shYAP cells phenocopy the behavior of FK866-resistant MDAMB231 cells (RES), a comparative proteomic study between these cells lines was performed. We identified a deregulation of cell cycle in both MDA shYAP and RES, which prevents apoptosis initiation upon FK866 treatment. Moreover, we found an upregulation of mitochondrial proteins, in line with an increased mitochondrial biogenesis, function and mass, as previously observed for RES. Overall, we showed a YAP-dependent rewiring of mitochondrial metabolism and cell cycle checkpoints, which sustains the acquirement of resistance to FK866 in TNBC.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Romina Belli

LAB HEAD: Provenzani Alessandro

PROVIDER: PXD046817 | Pride | 2025-02-24

REPOSITORIES: Pride

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			Action	DRS
	Provenzani_AGATA_MSWIL20233_2uL_13.raw	Raw
	Provenzani_AGATA_MSWIL20233_2uL_14.raw	Raw
	Provenzani_AGATA_MSWIL20233_2uL_15.raw	Raw
	Provenzani_AGATA_MSWIL20233_2uL_16.raw	Raw
	Provenzani_AGATA_MSWIL20233_2uL_17.raw	Raw

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Project description:Uncontrolled Transforming growth factor-beta (TGFβ) signaling promotes aggressive metastatic properties in late-stage breast cancers. However, how TGFβ-mediated cues are directed to induce late-stage tumorigenic events is poorly understood, particularly given that TGFβ has clear tumor suppressing activity in other contexts. Here we demonstrate that the transcriptional regulators TAZ and YAP (TAZ/YAP), key effectors of the Hippo pathway, are necessary to promote and maintain TGFβ-induced tumorigenic phenotypes in breast cancer cells. Interactions between TAZ/YAP, TGFβ-activated SMAD2/3, and TEAD transcription factors reveal convergent roles for these factors in the nucleus. Genome-wide expression analyses indicate that TAZ/YAP, TEADs and TGFβ-induced signals coordinate a specific pro-tumorigenic transcriptional program. Importantly, genes cooperatively regulated by TAZ/YAP, TEAD, and TGFβ, such as the novel targets NEGR1 and UCA1, are necessary for maintaining tumorigenic activity in metastatic breast cancer cells. Nuclear TAZ/YAP also cooperate with TGFβ signaling to promote phenotypic and transcriptional changes in non-tumorigenic cells to overcome TGFβ repressive effects. Our work thus identifies crosstalk between nuclear TAZ/YAP and TGFβ signaling in breast cancer cells, revealing novel insight into late-stage disease-driving mechanisms. Expression profiling was conducted following the repression of the transcriptional regulators TAZ and YAP (TAZ/YAP), the TEAD family of transcription factors (TEAD1/2/3/4), or the TGFb signaling pathway (with SB-431542, an inhibitor of the TBRI recpeptor) in human MDA-MB-231-LM2 breast cancer cells treated with TGFβ1. Human MDA-MB-231-LM2-4 breast cancer cells were transfected with control siRNA, or siRNAs targeting TAZ/YAP or all four TEADs and were treated 24 hours later with 500pM TGFβ1 or 5mM SB-431542 for an additional 24 hours. Total RNA was isolated and twelve microarrays in total were performed, with each condition carried out three times on separate days. The Boston University Microarray Core generated the data using the Affymetrix Human Gene 1.0 St Array.

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YAP modulates mitochondrial function and sensitive to NAMPT inhibition in triple negative breast cancer cells

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