Circadian lncRNA ADIRF-AS1 binds PBAF and regulates renal clear cell tumorigenesis
Rebekah Brooks, Judith Monzy, Bailey Aaron, Xue Zhang, Andrew V. Kossenkov, James E. Hayden, Frederick Keeney, David W. Speicher, Lin Zhang, Chi V. Dang
Abstract
We identify ADIRF-AS1 circadian long non-coding RNA (lncRNA). Deletion of ADIRF-AS1 in U2OS cells alters rhythmicity of clock-controlled genes and expression of extracellular matrix genes. ADIRF-AS1 interacts with all components of the PBAF (PBRM1/BRG1) complex in U2OS cells. Because PBRM1 is a tumor suppressor mutated in over 40% of clear cell renal carcinoma (ccRCC) cases, we evaluate ADIRF-AS1 in ccRCC cells. Reducing ADIRF-AS1 expression in ccRCC cells decreases expression of some PBAF-suppressed genes. Expression of these genes is partially rescued by PBRM1 loss, consistent with ADIRF-AS1 acting in part to modulate PBAF. ADIRF-AS1 expression correlates with survival in human ccRCC, particularly in PBRM1 wild-type, but not mutant, tumors. Loss of ADIRF-AS1 eliminates in vivo tumorigenesis, partially rescued by concurrent loss of PBRM1 only when co-injected with Matrigel, suggesting a PBRM1-independent function of ADIRF-AS1. Our findings suggest that ADIRF-AS1 functions partly through PBAF to regulate specific genes as a BMAL1-CLOCK-regulated, oncogenic lncRNA.