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Enhanced neovasculogenesis, especially vasculogenic mimicry (VM), contributes to the development of triple-negative breast cancer (TNBC). Breast tumor-initiating cells (BTICs) are involved in forming VM; however, the specific VM-forming BTIC population and the regulatory mechanisms remain undefined. We find that tumor endothelial marker 8 (TEM8) is abundantly expressed in TNBC and serves as a marker for VM-forming BTICs. Mechanistically, TEM8 increases active RhoC level and induces ROCK1-mediated phosphorylation of SMAD5, in a cascade essential for promoting stemness and VM capacity of breast cancer cells. ASB10, an estrogen receptor ERα trans-activated E3 ligase, ubiquitylates TEM8 for degradation, and its deficiency in TNBC resulted in a high homeostatic level of TEM8. In this work, we identify TEM8 as a functional marker for VM-forming BTICs in TNBC, providing a target for the development of effective therapies against TNBC targeting both BTIC self-renewal and neovasculogenesis simultaneously., Vasculogenic mimicry (VM) contributes to the development of triple-negative breast cancer. In this study, the authors show that TEM8 is expressed in VM-forming breast cancer stem cells and it promotes stemness and VM differentiation capacity through a RhoC/ROCK1/SMAD5 axis

The evolutionarily conserved Par3/Par6/aPKC complex regulates the polarity establishment of diverse cell types and distinct polarity-driven functions. However, how the Par complex is concentrated beneath the membrane to initiate cell polarization remains unclear. Here we show that the Par complex exhibits cell cycle-dependent condensation in Drosophila neuroblasts, driven by liquid–liquid phase separation. The open conformation of Par3 undergoes autonomous phase separation likely due to its NTD-mediated oligomerization. Par6, via C-terminal tail binding to Par3 PDZ3, can be enriched to Par3 condensates and in return dramatically promote Par3 phase separation. aPKC can also be concentrated to the Par3N/Par6 condensates as a client. Interestingly, activated aPKC can disperse the Par3/Par6 condensates via phosphorylation of Par3. Perturbations of Par3/Par6 phase separation impair the establishment of apical–basal polarity during neuroblast asymmetric divisions and lead to defective lineage development. We propose that phase separation may be a common mechanism for localized cortical condensation of cell polarity complexes., The evolutionarily conserved complex, the Par proteins, regulates cell polarity. Here, the authors show that in Drosophila neuroblasts, the Par complex exhibits liquid–liquid phase separation dependent on the cell cycle.

HECT E3 ligases control the degradation and functioning of numerous oncogenic/tumor-suppressive factors and signaling proteins, and their activities must be tightly regulated to prevent cancers and other diseases. Here we show that the Nedd4 family HECT E3 WWP1 adopts an autoinhibited state, in which its multiple WW domains sequester HECT using a multi-lock mechanism. Removing WW2 or WW34 led to a partial activation of WWP1. The structure of fully inhibited WWP1 reveals that many WWP1 mutations identified in cancer patients result in a partially active state with increased E3 ligase activity, and the WWP1 mutants likely promote cell migration by enhancement of ∆Np63α degradation. We further demonstrate that WWP2 and Itch utilize a highly similar multi-lock autoinhibition mechanism as that utilized by WWP1, whereas Nedd4/4 L and Smurf2 utilize a slightly variant version. Overall, these results reveal versatile autoinhibitory mechanisms that fine-tune the ligase activities of the HECT family enzymes., HECT type E3 ligases are key regulators of cell growth and proliferation. Here the authors present the crystal structures of the Nedd4 family E3 ligase WWP1 in a closed and semi-open state and in combination with mutagenesis experiments identify a multi-lock regulatory mechanism that allows the fine-tuning of activities of Nedd4 family E3 ligases.

It is well known that high-risk human papilloma virus (HR-HPV) infection is strongly associated with cervical cancer and E7 was identified as one of the key initiators in HPV-mediated carcinogenesis. Here we show that lactate dehydrogenase A (LDHA) preferably locates in the nucleus in HPV16-positive cervical tumors due to E7-induced intracellular reactive oxygen species (ROS) accumulation. Surprisingly, nuclear LDHA gains a non-canonical enzyme activity to produce α-hydroxybutyrate and triggers DOT1L (disruptor of telomeric silencing 1-like)-mediated histone H3K79 hypermethylation, resulting in the activation of antioxidant responses and Wnt signaling pathway. Furthermore, HPV16 E7 knocking-out reduces LDHA nuclear translocation and H3K79 tri-methylation in K14-HPV16 transgenic mouse model. HPV16 E7 level is significantly positively correlated with nuclear LDHA and H3K79 tri-methylation in cervical cancer. Collectively, our findings uncover a non-canonical enzyme activity of nuclear LDHA to epigenetically control cellular redox balance and cell proliferation facilitating HPV-induced cervical cancer development., High-risk human papilloma virus (HR-HPV) infection is strongly associated with cervical cancer and current evidences link E7 to HPV-associated carcinogenesis. Here the authors propose a model in which the infection of epithelial cells with high risk HPV results in a burst of reactive oxygen species, translocation of LDHA to the nucleus and activation of a gene profile that supports the growth of cervical cancer.

Besides the conventional carbon sources, acetyl-CoA has recently been shown to be generated from acetate in various types of cancers, where it promotes lipid synthesis and tumour growth. The underlying mechanism, however, remains largely unknown. We find that acetate induces a hyperacetylated state of histone H3 in hypoxic cells. Acetate predominately activates lipogenic genes ACACA and FASN expression by increasing H3K9, H3K27 and H3K56 acetylation levels at their promoter regions, thus enhancing de novo lipid synthesis, which combines with its function as the metabolic precursor for fatty acid synthesis. Acetyl-CoA synthetases (ACSS1, ACSS2) are involved in this acetate-mediated epigenetic regulation. More importantly, human hepatocellular carcinoma with high ACSS1/2 expression exhibit increased histone H3 acetylation and FASN expression. Taken together, this study demonstrates that acetate, in addition to its ability to induce fatty acid synthesis as an immediate metabolic precursor, also functions as an epigenetic metabolite to promote cancer cell survival under hypoxic stress., Cancer cells under stress use acetate to maintain the acetyl-CoA pool and fuel lipid biosynthesis. Here, the authors show that acetate also promotes de novo lipid synthesis by increasing histone acetylation at the promoters of lipogenic enzymes ACACA and FASN, thus inducing their expression.

Metabolic alteration is a hallmark of cancer. Dysregulation of methionine metabolism is implicated in human liver cancer. Methionine adenosyltransferase IIα (MAT IIα) is a key enzyme in the methionine cycle, catalysing the production of S-adenosylmethionine (SAM), a key methyl donor in cellular processes, and is associated with uncontrolled cell proliferation in cancer. Here we show that P300 acetylates MAT IIα at lysine residue 81 and destabilizes MAT IIα by promoting its ubiquitylation and subsequent proteasomal degradation. Conversely, histone deacetylase-3 deacetylates and stabilizes MAT IIα by preventing its proteasomal degradation. Folate deprivation upregulates K81 acetylation and destabilizes MAT IIα to moderate cell proliferation, whereas a single mutation at K81 reverses the proliferative disadvantage of cancer cells upon folate deprivation. Moreover, MAT IIα K81 acetylation is decreased in human hepatocellular cancer. Collectively, our study reveals a novel mechanism of MAT IIα regulation by acetylation and ubiquitylation, and a direct functional link of this regulation to cancer development., Folate plays an essential role in dividing cells and is regulated by methionine adenosyltransferase (MAT), where a switch from MAT Iα to MAT IIα expression seems to promote liver cancer progression. Here the authors demonstrate that MAT IIα stability is regulated by acetylation and this regulation is important for tumour growth.