Chromosome 3p Loss–Orchestrated VHL, HIF, and Epigenetic Deregulation in Clear Cell Renal Cell Carcinoma

Abstract

Clear cell renal cell carcinoma (ccRCC) is the most common renal cell carcinoma subtype, and metastatic ccRCC is associated with 5-year survival rates of 10% to 20%. Genetically, ccRCC originates from sequential losses of multiple tumor suppressor genes. Remarkably, chromosome 3p loss occurs in more than 90% of sporadic ccRCCs. This results in concurrent one-copy loss of four tumor suppressor genes that are also mutated individually at high frequency in ccRCC (ie, VHL, 80%; PBRM1, 29% to 46%; BAP1, 6% to 19%; and SETD2, 8% to 30%). Pathogenically, 3p loss probably represents the first genetic event that occurs in sporadic ccRCC and the second genetic event in VHL-mutated hereditary ccRCC. VHL constitutes the substrate recognition module of the VCB-Cul2 E3 ligase that degrades HIF1/2α, whereas PBRM1, BAP1, and SETD2 are epigenetic modulators that regulate gene transcription. Because 3p loss and VHL inactivation are nearly universal truncal events in ccRCC, the resulting HIF1/2 signaling overdrive and accompanied tumor hypervascularization probably underlie the therapeutic benefits observed with vascular endothelial growth factor receptor inhibitors, including sorafenib, sunitinib, pazopanib, axitinib, bevacizumab, cabozantinib, and lenvatinib. Furthermore, recent marked advances in ccRCC genomics, transcriptomics, proteomics, metabolomics, molecular mechanisms, mouse models, prognostic and predictive biomarkers, and clinical trials have rendered invaluable translational insights concerning precision kidney cancer therapeutics. With an armamentarium encompassing 13 drugs that exploit seven unique therapeutic mechanisms (ie, cytokines, vascular endothelial growth factor receptor, mTORC1, cMET/AXL, fibroblast growth factor receptor, programmed cell death-1 and programmed death-ligand 1, and cytotoxic T-cell lymphocyte associated-4) to treat metastatic renal cell carcinoma, one of the imminent clinical questions concerning care of patients with metastatic ccRCC is how a personalized treatment strategy, through rationally combining and sequencing different therapeutic modalities, can be formulated to offer the best clinical outcome for individual patients. Here, we attempt to integrate recent discoveries of immediate translational impacts and discuss future translational challenges and opportunities.

The role of ubiquitination in tumorigenesis and targeted drug discovery

“…HIF1, a transcription factor widely expressed under hypoxic conditions, is the key regulator of oxygen homeostasis in cells. 189 It can induce the expression of many glycolytic genes, such as glucose transporter member 1, hexokinase 1 and hexokinase 2, lactate dehydrogenase A, monocarboxylate transporters 4 and PDK1, which are indispensable in glucose uptake. HIFs include three subtypes: HIF1, HIF2 and HIF3.…”

Epigenetic crosstalk between hypoxia and tumor driven by HIF regulation

“…VHL loss is linked with HIFs over-expression within tumors, especially ccRCC, which observed in clinical trials, and thus small molecule inhibitors that target VHL are widely used in clinical studies [ 304 , 305 ]. VHL as a tumor suppressor mediates many cellular processes due to its multi-functional role, in which interacted with HIF signaling is the most notably physiological event that VHL binds to Elongin B, Elongin C, Cul2, and Rbx1 proteins forming E3 ligase, leading to HIF-α degradation inhibiting tumor progression [ 306 ].…”

The Therapeutic Landscape of Renal Cell Carcinoma: From the Dark Age to the Golden Age

“…7,10 Clear cell RCC is the most common subtype, comprising up to 70% to 75% of all new cases, 7,9,10 in which the tumorsuppressor von Hippel-Lindau (VHL) is nearly universally inactivated. 11,12 Patients with VHL syndrome inherit a mutant copy of VHL and are at increased risk for developing RCC. 13 Loss of VHL leads to the stabilization rather than degradation of hypoxia-inducible factor (HIF)1a and HIF2a, leading to pseudohypoxia and the activation of hypoxia-driven genes, including vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and other angiogenic and cell growth factors.…”

“…13 Loss of VHL leads to the stabilization rather than degradation of hypoxia-inducible factor (HIF)1a and HIF2a, leading to pseudohypoxia and the activation of hypoxia-driven genes, including vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and other angiogenic and cell growth factors. [9][10][11][14][15][16][17] Phosphoinositide 3-kinase (PI3K)-protein kinase B (AKT)−mammalian target of rapamycin (mTOR) (PI3K-AKT-mTor) pathway gene mutations also are common and were present in 28% of clear cell RCCs. 14,[18][19][20] pRCC accounts for approximately 10% to 15% of RCCs and can be subdivided into type 1 or type 2 pRCC.…”

“…6,9 Further refinement of these models to include molecular and genomic data would improve risk stratification to provide a better assessment of clinical course. 11,24 Moreover, better risk stratification could also reduce the future randomization bias of patients in clinical trials. 7…”