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Extensive knowledge has been gained on the transcription network controlled by ERα, however, the mechanism underlying ESR1 (encoding ERα) expression is less understood. We recently discovered that the Hippo pathway is required for the proper expression of ESR1. YAP/TAZ are transcription coactivators that are phosphorylated and inhibited by the Hippo pathway kinase LATS. Here we delineated the molecular mechanisms underlying ESR1 transcription repression by the Hippo pathway. Mechanistically, YAP binds to TEAD to increase local chromatin accessibility to stimulate transcription of nearby genes. Among the YAP target genes, Vestigial-Like Protein 3 (VGLL3) competes with YAP/TAZ for binding to TEAD transcription factor and recruits the NCOR2/SMRT repressor to the super-enhancer of ESR1 gene, leading to epigenetic alteration and transcriptional silencing. We developed a potent LATS inhibitor VT02956. Targeting the Hippo pathway by VT02956 represses ESR1 expression and inhibits the growth of ER+ breast cancer cells as well as patient-derived tumour organoids. Moreover, histone deacetylase inhibitors, such as Entinostat, induce VGLL3 expression to inhibit ER+ breast cancer cells. Our study suggests LATS as unexpected cancer therapeutic targets, especially for endocrine-resistant breast cancers.

Highlights In bone tissue engineering, polycaprolactone (PCL) has been extensively employed as a bone substitute due to its good biocompatibility, outstanding mechanical properties, controllable degradation rate, and excellent processability. However, PCL is a bioinert polymer with poor hydrophilicity, and it fails to actively induce new bone formation after implantation into the lesion. Therefore, it is generally necessary to find a bioactive material to improve these deficiencies of PCL. In this study, we first prepared a silicate‐based bioactive glass (SBG, 48SiO2‐24Na2O‐24CaO‐4P2O5, in mol%) using the melt‐quenching method, and then fabricated a series of PCL/SBG composite scaffolds with varying SBG powder contents (0, 10, 20, 30, and 40 wt.%) by 3D fiber deposition. The physico‐mechanical properties, mineralization capability, degradability and biological behavior of PCL/SBG scaffolds were systematically characterized. The results showed that the contact angle of the scaffolds decreased from 121.90 ± 3.74° to 86.29 ± 3.46° with the increase of SBG content, implying that the hydrophilicity was improved, and meanwhile the porosity and mechanical strength of PCL/SBG scaffolds first increased and then decreased, but they were within the range of human cancellous bone. Additionally, the degradation rate of PCL/SBG groups can be regulated by adjusting the SBG content. Finally, compared to the pure PCL group, the cell viability and alkaline phosphatase activity of MC3T3‐E1 on PCL/SBG groups were significantly enhanced. In the present work, the PCL/30SBG group exhibited great potential as a viable alternative to autografts and offers promising clinical applications for bone defect repair in the future. The addition of SBG powders accelerates the degradation of PCL. The addition of SBG powders enhances the hydrophilicity of PCL scaffolds. The degradation rate and bioactivity of PCL/SBG scaffolds can be regulated. The mechanical strength is within the range of human cancellous bone. PCL/30SBG shows improved cell viability and ALP activity. [ABSTRACT FROM AUTHOR]

The mechanistic target of rapamycin (mTOR) is a central cell growth controller and forms two distinct complexes: mTORC1 and mTORC2. mTORC1 integrates a wide range of upstream signals, both positive and negative, to regulate cell growth. Although mTORC1 activation by positive signals, such as growth factors and nutrients, has been extensively investigated, the mechanism of mTORC1 regulation by stress signals is less understood. In this study, we identified the Nemo-like kinase (NLK) as an mTORC1 regulator in mediating the osmotic and oxidative stress signals. NLK inhibits mTORC1 lysosomal localization and thereby suppresses mTORC1 activation. Mechanistically, NLK phosphorylates Raptor on S863 to disrupt its interaction with the Rag GTPase, which is important for mTORC1 lysosomal recruitment. Cells with Nlk deletion or knock-in of the Raptor S863 phosphorylation mutants are defective in the rapid mTORC1 inhibition upon osmotic stress. Our study reveals a function of NLK in stress-induced mTORC1 modulation and the underlying biochemical mechanism of NLK in mTORC1 inhibition in stress response.

The G protein-coupled estrogen receptor (GPER) mediates both the genomic and nongenomic effects of estrogen and has been implicated in breast cancer development. Here, we compared GPER expression in cancerous tissue and adjacent normal tissue in patients with invasive ductal carcinoma (IDC) of the breast and determined that GPER is highly upregulated in cancerous cells. Additionally, our studies revealed that GPER stimulation activates yes-associated protein 1 (YAP) and transcriptional coactivator with a PDZ-binding domain (TAZ), 2 homologous transcription coactivators and key effectors of the Hippo tumor suppressor pathway, via the Gαq-11, PLCβ/PKC, and Rho/ROCK signaling pathways. TAZ was required for GPER-induced gene transcription, breast cancer cell proliferation and migration, and tumor growth. Moreover, TAZ expression positively correlated with GPER expression in human IDC specimens. Together, our results suggest that the Hippo/YAP/TAZ pathway is a key downstream signaling branch of GPER and plays a critical role in breast tumorigenesis.

Glycolytic enzyme phosphoglycerate mutase (PGAM) plays an important role in coordinating energy production with generation of reducing power and the biosynthesis of nucleotide precursors and amino acids. Inhibition of PGAM by small RNAi or small molecule attenuates cell proliferation and tumor growth. PGAM activity is commonly upregulated in tumor cells, but how PGAM activity is regulated in vivo remains poorly understood. Here we report that PGAM is acetylated at lysine 100 (K100), an active site residue that is invariably conserved from bacteria, to yeast, plant, and mammals. K100 acetylation is detected in fly, mouse, and human cells and in multiple tissues and decreases PGAM2 activity. The cytosolic protein deacetylase sirtuin 2 (SIRT2) deacetylates and activates PGAM2. Increased levels of reactive oxygen species stimulate PGAM2 deacetylation and activity by promoting its interaction with SIRT2. Substitution of endogenous PGAM2 with an acetylation mimetic mutant K100Q reduces cellular NADPH production and inhibits cell proliferation and tumor growth. These results reveal a mechanism of PGAM2 regulation and NADPH homeostasis in response to oxidative stress that impacts cell proliferation and tumor growth.