昼夜节律长链非编码 RNA ADIRF-AS1 结合 PBAF 并调节肾透明细胞肿瘤发生。
Circadian lncRNA ADIRF-AS1 binds PBAF and regulates renal clear cell tumorigenesis.
机构信息
Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; The Wistar Institute, Philadelphia, PA, USA; The Ludwig Institute for Cancer Research, New York, NY, USA.
The Wistar Institute, Philadelphia, PA, USA; The Ludwig Institute for Cancer Research, New York, NY, USA.
出版信息
Cell Rep. 2022 Oct 18;41(3):111514. doi: 10.1016/j.celrep.2022.111514.
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.
我们鉴定出 ADIRF-AS1 昼夜节律性长非编码 RNA（lncRNA）。在 U2OS 细胞中敲除 ADIRF-AS1 会改变时钟控制基因的节律性和细胞外基质基因的表达。ADIRF-AS1 与 U2OS 细胞中 PBAF（PBRM1/BRG1）复合物的所有成分相互作用。由于 PBRM1 是超过 40%的透明细胞肾细胞癌（ccRCC）病例中的肿瘤抑制因子发生突变，因此我们在 ccRCC 细胞中评估了 ADIRF-AS1。在 ccRCC 细胞中降低 ADIRF-AS1 的表达会降低一些 PBAF 抑制基因的表达。这些基因的表达部分通过 PBRM1 缺失得到挽救，这与 ADIRF-AS1 部分调节 PBAF 的作用一致。ADIRF-AS1 的表达与人 ccRCC 的存活率相关，特别是在 PBRM1 野生型但不是突变型肿瘤中。缺失 ADIRF-AS1 消除了体内肿瘤发生，仅当与 Matrigel 同时缺失时才部分通过 PBRM1 缺失得到挽救，这表明 ADIRF-AS1 具有 PBRM1 独立的功能。我们的研究结果表明，ADIRF-AS1 部分通过 PBAF 作为 BMAL1-CLOCK 调节的致癌 lncRNA 来调节特定基因的功能。
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