Molecular Biology of Kidney Cancer

HIF activation causes synthetic lethality between the VHL tumor suppressor and the EZH1 histone methyltransferase

“…Suppression of HIF-dependent transcription under normoxic conditions is the canonical function of pVHL [3]. Strikingly, eliminating the obligate HIFα DNA-binding partner ARNT1 with CRISPR/Cas9 rescued the fitness defect caused by EZH1 loss in VHL- deficient cells (Fig.…”

“…When oxygen is low, EglN activity decreases and transcriptionally active HIFα accumulates. Deregulation of HIFα, and particularly HIF2α, drives the development of pVHL-defective ccRCC [3]. …”

“…VHL inactivation is an early “gatekeeper” event in ccRCC, but is not sufficient to cause ccRCC [3–6]. Additional genetic changes that cooperate with VHL loss to promote tumorigenesis include loss of chromosome 14q and gain of chromosome 5q [7, 8], as well as intragenic mutations that frequently affect chromatin regulators such as BAF180, BAF250, BRG1, BAP1, KDM6A, KDM5C, SETD2, and MLL3 [9–15].…”

On-target efficacy of a HIF-2α antagonist in preclinical kidney cancer models

“… Clear cell renal cell carcinoma (ccRCC), the most common form of kidney cancer, is usually linked to inactivation of the pVHL tumor suppressor protein and consequent accumulation of the HIF2α transcription factor 1 . Here we show that a small molecule (PT2399) that directly inhibits HIF2α causes tumor regression in preclinical models of primary and metastatic pVHL-defective ccRCC in an on-target fashion.…”

“…The current view that p53 mutations are uncommon in ccRCC is based mainly on studies of primary tumors removed at nephrectomy 1 . p53 pathway mutations might be more common in metastatic ccRCC, from which most ccRCC lines are derived, or might arise after ccRCC therapies 16 .…”