Autophagy degrades hypoxia inducible factors

DePavia, Adela; Jonasch, Eric; Liu, Xian De

doi:10.1080/23723556.2015.1104428

Cited by 12 publications

(13 citation statements)

References 8 publications

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“…HIF1α protein turnover is driven by several pathways, the best characterized of which involves oxygen-dependent interaction with the vHL ubiquitin ligase ( Ivan and Kaelin, 2017 ). HIF1α is also subject to autophagic degradation by both vHL-dependent and vHL-independent mechanisms ( DePavia et al., 2016 ). Recently, it was demonstrated that CRYs are also susceptible to degradation via macroautophagy ( Toledo et al., 2018 ).…”

Section: Discussionmentioning

confidence: 99%

Cryptochromes Suppress HIF1α in Muscles

et al. 2020

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Summary Muscles preferentially utilize glycolytic or oxidative metabolism depending on the intensity of physical activity. Transcripts required for carbohydrate and lipid metabolism undergo circadian oscillations of expression in muscles, and both exercise capacity and the metabolic response to exercise are influenced by time of day. The circadian repressors CRY1 and CRY2 repress peroxisome proliferator-activated receptor delta (PPARδ), a major driver of oxidative metabolism and exercise endurance. CRY-deficient mice exhibit enhanced PPARδ activation and greater maximum speed when running on a treadmill but no increase in exercise endurance. Here we demonstrate that CRYs limit hypoxia-responsive transcription via repression of HIF1α-BMAL1 heterodimers. Furthermore, CRY2 appeared to be more effective than CRY1 in the reduction of HIF1α protein steady-state levels in primary myotubes and quadriceps in vivo . Finally, CRY-deficient myotubes exhibit metabolic alterations consistent with cryptochrome-dependent suppression of HIF1α, which likely contributes to circadian modulation of muscle metabolism.

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Section: Discussionmentioning

confidence: 99%

Cryptochromes Suppress HIF1α in Muscles

et al. 2020

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“…tFeb's regulation of MΦs is partially dependent on autophagy TFEB is a key regulator of autophagy and lysosome biogenesis, 20 activation are known to counteract NLRP3 inflammasome activity 15 and mediate HIF-1α degradation. 16 PI3K is required for autophagy and its inhibitor LY294002 can inhibit autophagic sequestration, a required first step of autophagy. 31 Therefore, we aimed to examine if autophagy inhibition by LY294002 could negate the impact of TFEB overexpression on MΦs.…”

Section: Mφ Tfeb Ablation Promotes Breast Tumor Growthmentioning

confidence: 99%

“…15 Autophagy also may lead to degradation of HIF-1α, de-escalating the hypoxia signaling cascade. 16 Because TAMs are equipped with a wide range of protumor effector molecules, and MΦs are the first line of defense against infection, TAM-targeting cancer treatment strategies via depleting MΦs or inhibiting a single type of molecule are either harmful or insufficient. Targeting TAMs at a critical point to keep multiple protumor pathways in check would be more desirable.…”

Section: Introductionmentioning

confidence: 99%

TFEB is a master regulator of tumor-associated macrophages in breast cancer

Hodge

Liu

et al. 2020

J Immunother Cancer

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BackgroundTumor-associated macrophages (TAMs) play key roles in the development of many malignant solid tumors including breast cancer. They are educated in the tumor microenvironment (TME) to promote tumor growth, metastasis, and therapy resistance. However, the phenotype of TAMs is elusive and how to regulate them for therapeutic purpose remains unclear; therefore, TAM-targeting therapies have not yet achieved clinical success. The purposes of this study were to examine the role of transcription factor EB (TFEB) in regulating TAM gene expression and function and to determine if TFEB activation can halt breast tumor development.MethodsMicroarrays were used to analyze the gene expression profile of macrophages (MΦs) in the context of breast cancer and to examine the impact of TFEB overexpression. Cell culture studies were performed to define the mechanisms by which TFEB affects MΦ gene expression and function. Mouse studies were carried out to investigate the impact of MΦ TFEB deficiency or activation on breast tumor growth. Human cancer genome data were analyzed to reveal the prognostic value of TFEB and its regulated genes.ResultsTAM-mimic MΦs display a unique gene expression profile, including significant reduction in TFEB expression. TFEB overexpression favorably modulates TAM gene expression through multiple signaling pathways. Specifically, TFEB upregulates suppressor of cytokine signaling 3 (SOCS3) and peroxisome proliferator-activated receptor γ (PPARγ) expression and autophagy/lysosome activities, inhibits NLRP3 (NLR Family Pyrin Domain Containing 3) inflammasome and hypoxia-inducible factor (HIF)-1α mediated hypoxia response, and thereby suppresses an array of effector molecules in TAMs including arginase 1, interleukin (IL)-10, IL-1β, IL-6 and prostaglandin E2. MΦ-specific TFEB deficiency promotes, while activation of TFEB using the natural disaccharide trehalose halts, breast tumor development by modulating TAMs. Analysis of human patient genome database reveals that expression levels of TFEB, SOCS3 and PPARγ are positive prognostic markers, while HIF-1α is a negative prognostic marker of breast cancer.ConclusionsOur study identifies TFEB as a master regulator of TAMs in breast cancer. TFEB controls TAM gene expression and function through multiple autophagy/lysosome-dependent and independent pathways. Therefore, pharmacological activation of TFEB would be a promising therapeutic approach to improve the efficacy of existing treatment including immune therapies for breast cancer by favorably modulating TAM function and the TME.

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“…Equivalently, it appears that HIF-1 possesses diverse regulatory roles in autophagy activation (Mazure and Pouyssegur, 2010 ). Interestingly rather than being regulated by HIF-1, autophagy per se , can regulate HIF-1 stability (DePavia et al, 2016 ). This reciprocal regulation of autophagy and HIF-1 activity can account for opposing roles of autophagy activation in various human tumors.…”

Section: Introductionmentioning

confidence: 99%

Hypoxia and Selective Autophagy in Cancer Development and Therapy

Daskalaki

Gkikas

Tavernarakis

2018

Front. Cell Dev. Biol.

133

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Low oxygen availability, a condition known as hypoxia, is a common feature of various pathologies including stroke, ischemic heart disease, and cancer. Hypoxia adaptation requires coordination of intricate pathways and mechanisms such as hypoxia-inducible factors (HIFs), the unfolded protein response (UPR), mTOR, and autophagy. Recently, great effort has been invested toward elucidating the interplay between hypoxia-induced autophagy and cancer cell metabolism. Although novel types of selective autophagy have been identified, including mitophagy, pexophagy, lipophagy, ERphagy and nucleophagy among others, their potential interface with hypoxia response mechanisms remains poorly understood. Autophagy activation facilitates the removal of damaged cellular compartments and recycles components, thus promoting cell survival. Importantly, tumor cells rely on autophagy to support self-proliferation and metastasis; characteristics related to poor disease prognosis. Therefore, a deeper understanding of the molecular crosstalk between hypoxia response mechanisms and autophagy could provide important insights with relevance to cancer and hypoxia-related pathologies. Here, we survey recent findings implicating selective autophagy in hypoxic responses, and discuss emerging links between these pathways and cancer pathophysiology.

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Autophagy degrades hypoxia inducible factors

Cited by 12 publications

References 8 publications

Cryptochromes Suppress HIF1α in Muscles

Cryptochromes Suppress HIF1α in Muscles

TFEB is a master regulator of tumor-associated macrophages in breast cancer

Hypoxia and Selective Autophagy in Cancer Development and Therapy

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