Intracellular cholesterol biosynthesis in enchondroma and chondrosarcoma

Zhang, Hongyuan; Wei, Qingxia; Tsushima, Hiroyuki; Puviindran, Vijitha; Tang, Yuning J.; Pathmanapan, Sinthu; Poon, Raymond; Ramu, Eyal; Al‐Jazrawe, Mushriq; Wunder, Jay S.; Alman, Benjamin A.

doi:10.1172/jci.insight.127232

Cited by 15 publications

(18 citation statements)

References 36 publications

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“…In this study, we showed that these IDH mutations are directly implicated in the stabilization of HIF-2α in chondrosarcoma cells. Recently, Alman and colleagues have linked cholesterol biosynthesis to the tumorigenesis of IDH mutation-driven chondrosarcoma 58 . Our transcriptome analysis indicated that genes involved in the cholesterol synthesis pathway were significantly regulated by HIF-2α in chondrosarcoma cells.…”

Section: Discussionmentioning

confidence: 99%

A system-level approach identifies HIF-2α as a critical regulator of chondrosarcoma progression

et al. 2020

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Chondrosarcomas, malignant cartilaginous neoplasms, are capable of transitioning to highly aggressive, metastatic, and treatment-refractory states, resulting in significant patient mortality. Here, we aim to uncover the transcriptional program directing such tumor progression in chondrosarcomas. We conduct weighted correlation network analysis to extract a characteristic gene module underlying chondrosarcoma malignancy. Hypoxia-inducible factor-2α (HIF-2α, encoded by EPAS1) is identified as an upstream regulator that governs the malignancy gene module. HIF-2α is upregulated in high-grade chondrosarcoma biopsies and EPAS1 gene amplification is associated with poor prognosis in chondrosarcoma patients. Using tumor xenograft mouse models, we demonstrate that HIF-2α confers chondrosarcomas the capacities required for tumor growth, local invasion, and metastasis. Meanwhile, pharmacological inhibition of HIF-2α, in conjunction with the chemotherapy agents, synergistically enhances chondrosarcoma cell apoptosis and abolishes malignant signatures of chondrosarcoma in mice. We expect that our insights into the pathogenesis of chondrosarcoma will provide guidelines for the development of molecular targeted therapeutics for chondrosarcoma.

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Section: Discussionmentioning

confidence: 99%

A system-level approach identifies HIF-2α as a critical regulator of chondrosarcoma progression

et al. 2020

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“…Comparative analysis of the transcriptomes revealed that PROM1 regulates the defined targets and suggested that cholesterol metabolism is potentially a cellular physiological process that can be manipulated to potentiate neuronal regeneration. To test this hypothesis, we first tested the cellular cholesterol level from the DRG neurons using a filipin staining assay ( 68 , 69 ) and found that the cholesterol level is significantly reduced by PROM1 overexpression ( Fig. 6 A and B ), indicating that the transcriptional down-regulation of the cholesterol metabolism genes by PROM1 overexpression results in a reduction in neuronal cholesterol.…”

Section: Resultsmentioning

confidence: 99%

The stem cell marker Prom1 promotes axon regeneration by down-regulating cholesterol synthesis via Smad signaling

Lee

Shin

Lee

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Axon regeneration is regulated by a neuron-intrinsic transcriptional program that is suppressed during development but that can be reactivated following peripheral nerve injury. Here we identifyProm1, which encodes the stem cell marker prominin-1, as a regulator of the axon regeneration program.Prom1expression is developmentally down-regulated, and the genetic deletion ofProm1in mice inhibits axon regeneration in dorsal root ganglion (DRG) cultures and in the sciatic nerve, revealing the neuronal role ofProm1in injury-induced regeneration. Elevating prominin-1 levels in cultured DRG neurons or in mice via adeno-associated virus-mediated gene delivery enhances axon regeneration in vitro and in vivo, allowing outgrowth on an inhibitory substrate.Prom1overexpression induces the consistent down-regulation of cholesterol metabolism-associated genes and a reduction in cellular cholesterol levels in a Smad pathway-dependent manner, which promotes axonal regrowth. We find that prominin-1 interacts with the type I TGF-β receptor ALK4, and that they synergistically induce phosphorylation of Smad2. These results suggest thatProm1and cholesterol metabolism pathways are possible therapeutic targets for the promotion of neural recovery after injury.

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“…Little is known about the metabolism of chondrocytes and the metabolism of chondrosarcomas. However, studies have suggested that mitochondrial metabolism may be important since it has been shown that isocitrate dehydrogenase mutations are common in chondrosarcoma and occur in approximately 50% of cases and there have also been reports of high glutaminolysis activity, high NAD flux, activation of the mTOR pathway as well as alterations in lipid metabolism in chondrosarcoma [43] [47]. However, other studies in chondrosarcomas based on expression analysis have suggested that glycolysis might be increased or OXPHOS reduced [48] [49].…”

Section: Discussionmentioning

confidence: 99%

Translocase of the outer mitochondrial membrane complex subunit 20 (TOMM20) facilitates cancer aggressiveness and therapeutic resistance in chondrosarcoma

Roche¹,

Zhao²,

Whitaker‐Menezes³

et al. 2020

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Highlights  High-grade human chondrosarcomas have higher expression of translocase of the outer mitochondrial membrane complex subunit 20 (TOMM20) than low-grade tumors.  TOMM20 overexpression in chondrosarcoma cells increases markers of mitochondrial reprogramming, proliferation, and resistance to apoptosis.  TOMM20 overexpression in chondrosarcoma induces resistance to anticancer drugs.  TOMM20 overexpression in chondrosarcoma cells induces larger tumors in vivo.

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Intracellular cholesterol biosynthesis in enchondroma and chondrosarcoma

Cited by 15 publications

References 36 publications

A system-level approach identifies HIF-2α as a critical regulator of chondrosarcoma progression

A system-level approach identifies HIF-2α as a critical regulator of chondrosarcoma progression

The stem cell marker Prom1 promotes axon regeneration by down-regulating cholesterol synthesis via Smad signaling

Translocase of the outer mitochondrial membrane complex subunit 20 (TOMM20) facilitates cancer aggressiveness and therapeutic resistance in chondrosarcoma

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