HIF1α and HIF2α: sibling rivalry in hypoxic tumour growth and progression

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210

Dysregulation of the von Hippel-Lindau/hypoxia-inducible transcription factor (HIF) signaling pathway promotes clear cell renal cell carcinoma (ccRCC) progression and metastasis. The protein kinase GAS6/AXL signaling pathway has recently been implicated as an essential mediator of metastasis and receptor tyrosine kinase crosstalk in cancer. Here we establish a molecular link between HIF stabilization and induction of AXL receptor expression in metastatic ccRCC. We found that HIF-1 and HIF-2 directly activate the expression of AXL by binding to the hypoxia-response element in the AXL proximal promoter. Importantly, genetic and therapeutic inactivation of AXL signaling in metastatic ccRCC cells reversed the invasive and metastatic phenotype in vivo. Furthermore, we define a pathway by which GAS6/AXL signaling uses lateral activation of the met proto-oncogene (MET) through SRC proto-oncogene nonreceptor tyrosine kinase to maximize cellular invasion. Clinically, AXL expression in primary tumors of ccRCC patients correlates with aggressive tumor behavior and patient lethality. These findings provide an alternative model for SRC and MET activation by growth arrest-specific 6 in ccRCC and identify AXL as a therapeutic target driving the aggressive phenotype in renal clear cell carcinoma.targeted therapy | kidney cancer | VHL | hepatocellular carcinoma K idney cancer is a leading cause of cancer-related deaths in the United States. Metastasis to distant organs including the lung, bone, liver, and brain is the primary cause of death in kidney cancer patients, as only 12% of patients with metastatic kidney cancer will survive past 5 y, in comparison with 92% of patients with a localized disease (1). Because kidney cancer is chemo-and radiation-resistant, targeted therapies are needed for the prevention and management of metastatic kidney cancer.The von Hippel-Lindau (VHL)-hypoxia-inducible transcription factor (HIF) pathway is a critical regulator of clear cell renal cell carcinoma (ccRCC) tumor initiation and metastasis. VHL is a classic tumor suppressor controlling tumor initiation in ∼90% of ccRCC tumors (2, 3). VHL is the substrate recognition component of an E3 ubiquitin ligase complex containing the elongins B and C (4, 5), Cullin-2 (6), and Rbx1 (7) that targets the hydroxylated, oxygen-sensitive α-subunits of HIFs (HIF-1, -2, and -3) for ubiquitination and degradation by the 26S proteasome (8, 9). Thus, the primary function ascribed to VHL is the regulation of HIF protein stability. In VHL-deficient tumors, HIF transcriptional activity is constitutively active and contributes to both ccRCC tumor initiation and metastasis (8-11). Although many downstream HIF targets controlling ccRCC tumor initiation have been defined, key targets involved in ccRCC metastasis remain to be identified.AXL, a member of the TAM family of receptor tyrosine kinases (RTKs), has recently been described as an essential mediator of cancer metastasis. Additionally, AXL has been reported to mediate RTK crosstalk and resistance to targeted kina...

Section: Resultsmentioning

confidence: 99%

Direct regulation of GAS6/AXL signaling by HIF promotes renal metastasis through SRC and MET

Rankin

Fuh

Castellini

et al. 2014

242

210

“…Such neovascularization through HIF1α-induced VEGF is activated in tumor growth, ischemic collateral formation, and wound healing (12)(13)(14). HIF1α is also reportedly activated and functions in tumor development in renal cell carcinoma (15).…”

mentioning

confidence: 99%

HIF1α is required for osteoclast activation by estrogen deficiency in postmenopausal osteoporosis

Miyauchi

Sato²,

Kobayashi³

et al. 2013

Self Cite

166

160

In women, estrogen deficiency after menopause frequently accelerates osteoclastic bone resorption, leading to osteoporosis, the most common skeletal disorder. However, mechanisms underlying osteoporosis resulting from estrogen deficiency remain largely unknown. Here we show that in bone-resorbing osteoclasts, estrogendependent destabilization of hypoxia-inducible factor 1 alpha (HIF1α), which is unstable in the presence of oxygen, plays a pivotal role in promoting bone loss in estrogen-deficient conditions. In vitro, HIF1α was destabilized by estrogen treatment even in hypoxic conditions, and estrogen loss in ovariectomized (Ovx) mice stabilized HIF1α in osteoclasts and promoted their activation and subsequent bone loss in vivo. Osteoclast-specific HIF1α inactivation antagonized bone loss in Ovx mice and osteoclast-specific estrogen receptor alpha deficient mice, both models of estrogen-deficient osteoporosis. Oral administration of a HIF1α inhibitor protected Ovx mice from osteoclast activation and bone loss. Thus, HIF1α represents a promising therapeutic target in osteoporosis.B one mass is tightly regulated by a delicate balance between osteoblastic bone formation and osteoclastic bone resorption. Estrogen loss in women after menopause frequently promotes activation of osteoclastic bone resorption, causing osteoporosis. Osteoporotic bone phenotypes are seen in ovariectomized female mice, and estrogen deficiency-induced bone loss in both mouse models and women is ameliorated by estrogen treatment (1, 2). However, estrogen administration reportedly increases risk of cardiovascular events and carcinogenesis of the mammary gland and uterus (3). Bioavailable estrogens including selective estrogen receptor modulators (SERMs) also protect bone from estrogen deficiency-induced osteoporosis (4), and estrogen and SERMs primarily act via estrogen receptors (ER), ERα and ERβ (5, 6). However, how SERMs act on bone remains largely unknown. Thus, understanding of osteoclast activation following estrogen loss is crucial for development of safe therapeutic reagents.Both the endosteal zone of bone marrow cavities and epiphyseal growth plates are hypoxic areas, and the hypoxia-inducible factor (HIF) signaling pathway governs chondrocyte and osteoblast function in these respective areas (7,8). The HIF1 transcription factor consists of an oxygen-regulated alpha subunit, HIF1α, and a constitutively expressed beta subunit, HIF1β. Under normoxia, HIF1α is posttranslationally modified by prolyl hydroxylases, which catalyze hydroxylation of proline residues in the presence of O 2 and Fe 2+ . Recognition of hydroxylated HIF1α by the von Hippel-Lindau tumor suppressor protein recruits an E3 ubiquitin ligase complex targeting HIF1α for proteasomal degradation. Conversely, under hypoxia, proline hydroxylation is inhibited by substrate (O 2 ) deprivation, allowing HIF1α accumulation and formation of an active transcriptional complex with HIF1β (9). Recently, regulation of HIF1α protein levels by factors other than O 2 , including reactive ...

“…HIF-1 directly controls the expression of crucial genes involved in proliferation/survival (IGF2, PDGFB), metabolism (GLUTs, HKs), angiogenesis (VEGF-A, PDGFB, ANGPTs), and metastasis (ZEB-1, MMP9). This transcriptional switch is an important determinant of tumor progression (5). Increased HIF-1α levels in cancer cells can be a result of either intratumoral hypoxia or the altered function of tumor suppressors and oncogenes.…”

mentioning

confidence: 99%

TAp73 opposes tumor angiogenesis by promoting hypoxia-inducible factor 1α degradation

Amelio

Inoue

Markert

et al. 2014

100

Tumor hypoxia and hypoxia-inducible factor 1 (HIF-1) activation are associated with cancer progression. Here, we demonstrate that the transcription factor TAp73 opposes HIF-1 activity through a nontranscriptional mechanism, thus affecting tumor angiogenesis. TAp73-deficient mice have an increased incidence of spontaneous and chemically induced tumors that also display enhanced vascularization. Mechanistically, TAp73 interacts with the regulatory subunit (α) of HIF-1 and recruits mouse double minute 2 homolog into the protein complex, thus promoting HIF-1α polyubiquitination and consequent proteasomal degradation in an oxygen-independent manner. In human lung cancer datasets, TAp73 strongly predicts good patient prognosis, and its expression is associated with low HIF-1 activation and angiogenesis. Our findings, supported by in vivo and clinical evidence, demonstrate a mechanism for oxygen-independent HIF-1 regulation, which has important implications for individualizing therapies in patients with cancer.