3091

HIF1A

HIF-1A|HIF-1alpha|HIF1|HIF1-ALPHA|MOP1|PASD8|bHLHe78;hypoxia inducible factor 1, alpha subunit (basic helix-loop-helix transcription factor);HIF1A;hypoxia inducible factor 1, alpha subunit (basic helix-loop-helix transcription factor)

ARNT interacting protein|ARNT-interacting protein|HIF-1-alpha|PAS domain-containing protein 8|basic-helix-loop-helix-PAS protein MOP1|class E basic helix-loop-helix protein 78|hypoxia-inducible factor 1 alpha isoform I.3|hypoxia-inducible factor 1, alpha

14q23.2

protein-coding

Mel-18 has been implicated in several processes in tumor progression, in which the Akt pathway is involved as an important key molecular event. However, the function of Mel-18 in human cancers has not been fully established yet. Here, we examined the effect of Mel-18 on tumor angiogenesis in human breast cancer, and found that Mel-18 was a novel regulator of HIF-1alpha. Mel-18 negatively regulated the HIF-1alpha expression and its target gene VEGF transcription during both normoxia and hypoxia. We demonstrated that Mel-18 regulated the HIF-1alpha expression and activity via the PI3K/Akt pathway. Loss of Mel-18 downregulated Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expression, consequently activating the PI3K/Akt/MDM2 pathway, and leading to an increase of HIF-1alpha protein level. Mel-18 modulated the HIF-1alpha transcriptional activity via regulating the cytoplasmic retention of FOXO3a, a downstream effector of Akt, and recruitment of HIF-1alpha/CBP complex to the VEGF promoter. Furthermore, our data shows that Mel-18 blocked tumor angiogenesis both in vitro and in vivo. Mel-18 overexpression inhibited in vitro tube formation in human umbilical endothelial cells (HUVECs). Xenografts in NOD/SCID mice derived from stably Mel-18 knocked down MCF7 human breast cancer cells showed increased tumor volume, microvessel density, and phospho-Akt and HIF-1alpha expression levels. In conclusion, our findings provide that Mel-18 is a novel regulator of tumor angiogenesis through regulating HIF-1alpha and its target VEGF expressions mediated by the PTEN/PI3K/Akt pathway, suggesting a new tumor-suppressive role of Mel-18 in human breast cancer.

The Hippo pathway regulates contact inhibition of cell proliferation and, ultimately, organ size in diverse multicellular organisms. Inactivation of the Hippo pathway promotes nuclear localization of the transcriptional coactivator Yap1, a Hippo pathway effector, and can cause cancer. Here, we show that deletion of alphaE (alpha epithelial) catenin in the hair follicle stem cell compartment resulted in the development of skin squamous cell carcinoma in mice. Tumor formation was accelerated by simultaneous deletion of alphaE-catenin and the tumor suppressor-encoding gene p53. A small interfering RNA screen revealed a functional connection between alphaE-catenin and Yap1. By interacting with Yap1, alphaE-catenin promoted its cytoplasmic localization, and Yap1 showed constitutive nuclear localization in alphaE-catenin-null cells. We also found an inverse correlation between alphaE-catenin abundance and Yap1 activation in human squamous cell carcinoma tumors. These findings identify alphaE-catenin as a tumor suppressor that inhibits Yap1 activity and sequesters it in the cytoplasm.

Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that promotes angiogenesis, metabolic reprogramming, and other critical aspects of cancer biology. The four-and-a-half LIM domain (FHL) proteins are a family of LIM domain-only proteins implicated in transcriptional regulation and suppression of tumor growth. Here we describe functional interactions between the FHL proteins and HIF-1. FHL1-3 inhibit HIF-1 transcriptional activity and HIF-1alpha transactivation domain function by oxygen-independent mechanisms. FHL2 directly interacts with HIF-1alpha to repress transcriptional activity. FHL1 binds to the p300/CBP co-activators and disrupts binding with HIF-1alpha. FHL3 does not bind to HIF-1alpha or p300, indicating that it regulates transactivation by a novel molecular mechanism. expression of the FHL proteins increased upon HIF-1alpha induction, suggesting the existence of a feedback loop. These results identify FHL proteins as negative regulators of HIF-1 activity, which may provide a mechanism by which they suppress tumor growth.

Hypoxia-inducible factor (HIF) 1alpha and 2alpha are transcription factors responsible for the cellular response to hypoxia. The functional roles of HIF1alpha and HIF2alpha in cancer are distinct and vary among different tumor types. The aim of this study was to evaluate the compartment-specific role(s) of HIF1alpha and HIF2alpha in breast cancer. To this end, immortalized human fibroblasts and MDA-MB-231 breast cancer cells carrying constitutively active HIF1alpha or HIF2alpha mutants were analyzed with respect to their metabolic function(s) and ability to promote tumor growth in an in vivo setting. We observed that activation of HIF1alpha, but not HIF2alpha, in stromal cells promotes a shift toward aerobic glycolysis, with increased L-lactate production and a loss of mitochondrial activity. In a xenograft model, HIF1alpha-activated fibroblasts promoted the tumor growth of co-injected MDA-MB-231 cells without an increase in angiogenesis. Conversely, HIF2alpha-activated stromal cells did not favor tumor growth and behaved as the empty vector controls. Similarly, activation of HIF1alpha, but not HIF2alpha, in MDA-MB-231 cells promoted a shift toward aerobic glycolysis, with increased glucose uptake and L-lactate production. In contrast, HIF2alpha activation in cancer cells increased the expression of EGFR, Ras and cyclin D1, which are known markers of tumor growth and cell cycle progression. In a xenograft model, HIF1alpha activation in MDA-MB-231 cells acted as a tumor suppressor, resulting in an almost 2-fold reduction in tumor mass and volume. Interestingly, HIF2alpha activation in MDA-MB-231 cells induced a significant ~2-fold-increase in tumor mass and volume. Analysis of mitochondrial activity in these tumor xenografts using COX (cytochrome C oxidase) staining demonstrated elevated mitochondrial oxidative metabolism (OXPHOS) in HIF2alpha-tumors. We conclude that the role(s) of HIF1alpha and HIF2alpha in tumorigenesis are compartment-specific. HIF1alpha acts as a tumor promoter in stromal cells but as a tumor suppressor in cancer cells. Conversely, HIF2alpha is a tumor promoter in cancer cells. Mechanistically, HIF1alpha-driven aerobic glycolysis in stromal cells supports cancer cell growth via the paracrine production of nutrients (such as L-lactate) that can "feed" cancer cells. However, HIF1alpha-driven aerobic glycolysis in cancer cells inhibits tumor growth. Finally, HIF2alpha activation in cancer cells induces the expression of known pro-oncogenic molecules and promotes the mitochondrial activity of cancer cells.

Hypoxia occurs frequently in human cancers and induces adaptive changes in cell metabolism that include a switch from oxidative phosphorylation to glycolysis, increased glycogen synthesis, and a switch from glucose to glutamine as the major substrate for fatty acid synthesis. This broad metabolic reprogramming is coordinated at the transcriptional level by HIF-1, which functions as a master regulator to balance oxygen supply and demand. HIF-1 is also activated in cancer cells by tumor suppressor (e.g., VHL) loss of function and oncogene gain of function (leading to PI3K/AKT/mTOR activity) and mediates metabolic alterations that drive cancer progression and resistance to therapy. Inhibitors of HIF-1 or metabolic enzymes may impair the metabolic flexibility of cancer cells and make them more sensitive to anticancer drugs.