ANGPTL4 suppress clear cell renal cell carcinoma via inhibition lysosomal acid lipase

Renal cell carcinoma (RCC), the most common form of kidney cancer, is a heterogeneous disease with clear cell RCC (ccRCC) being the most prevalent and aggressive subtype. While most ccRCC tumors have elevated expression of angiopoietin-like 4 (ANGPTL4), in our study we identified a significant subset of patients whose cancers show no increase in ANGPTL4 expression. These patients have a worse prognosis compared to the patients with high expression of ANGPTL4. These ANGPTL4-low cancers are characterized by the increased frequency of wild-type Von Hippel-Lindau (wt VHL), a gene that is commonly mutated in ccRCC, and an enrichment for genes associated with lipid metabolism. Using RCC tumor models with wild type VHL, we demonstrate that ANGPTL4 behaves as a tumor suppressor. The loss of ANGPTL4 in ccRCC cell lines results in increased tumor growth and colony formation in a lysosomal acid lipase (LAL)-dependent manner, a phenotype rescued by the expression of N-terminus ANGPTL4. At the mechanistic level, the loss of ANGPTL4 increases lysosomal acid lipase activity in ccRCC cells. This data suggests that ANGPTL4 enacts its tumor-suppressive effects in ccRCC by regulating LAL activity. Importantly, the identified patient cohort with low ANGPTL4 expression may exhibit increased reliance on lipid metabolism, which can be a point of target for future therapy. Overall design: To investigate transcriptional changes as a result of loss of ANGPTL4. Human ccRCC cell lines, 786O and CAKi-1, were directly transfected with Caspase 9 protein and a single guide RNA for ANGPTL4 to generation pools of knockouit cells. Single clones were grown and clones with loss of ANGPTL4 mRNA were combined to generate ANGPTL4 knockout (KO)( cells. Clones without loss of ANGPTL4 were combined to gnerate wild type (WT) cells. Comparative gene expression profiling was perfromed from RNAseq of 4 WT and 5 KO CAKI-1 replicates and 3 WT and 3 KO 786O replicates.