Georgetown-Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University Medical Center, Washington, DC, USA.
Flow Cytometry Shared Resource, Georgetown University Medical Center, Washington, DC, USA.
Int J Biol Sci. 2022 Mar 28;18(7):2670-2682. doi: 10.7150/ijbs.69615. eCollection 2022.
Retinoic acid receptor responder 1 (RARRES1) is among the most commonly methylated loci in multiple cancers. RARRES1 regulates mitochondrial and fatty acid metabolism, stem cell differentiation, and survival of immortalized cell lines . Here, we created constitutive knockout () mouse models to study RARRES1 function . embryonic fibroblasts regulated tubulin glutamylation, cell metabolism, and survival, recapitulating RARRES1 function in immortalized cell lines. In two mouse strains, loss of led to a markedly increased dose-dependent incidence of follicular lymphoma (FL). Prior to lymphoma formation, B cells have compromised activation, maturation, differentiation into antibody-secreting plasma cells, and cell cycle progression. ablation increased B cell survival and led to activation of the unfolded protein response (UPR) and heat shock response (HSR). deficiency had differential effects on cellular metabolism, with increased bioenergetic capacity in fibroblasts, and minor effects on bioenergetics and metabolism in B cells. These findings reveal that RARRES1 is a bona fide tumor suppressor and the deletion in mice promotes cell survival, and reduces B cell differentiation with B cell autonomous and non-autonomous functions.
维甲酸受体应答基因 1（RARRES1）是多种癌症中甲基化频率最高的基因之一。RARRES1 调节线粒体和脂肪酸代谢、干细胞分化和永生化细胞系的存活。在这里，我们构建了组成型 RARRES1 基因敲除（）小鼠模型，以研究 RARRES1 的功能。RARRES1 缺失的胚胎成纤维细胞调节微管蛋白谷氨酸化、细胞代谢和存活，重现了 RARRES1 在永生化细胞系中的功能。在两种小鼠品系中，缺失导致滤泡性淋巴瘤（FL）的发生呈显著的、剂量依赖性增加。在淋巴瘤形成之前，B 细胞的激活、成熟、分化为分泌抗体的浆细胞以及细胞周期进程受损。缺失增加了 B 细胞的存活，并导致未折叠蛋白反应（UPR）和热休克反应（HSR）的激活。缺失对细胞代谢有不同的影响，成纤维细胞的生物能量能力增加，而 B 细胞的生物能量和代谢影响较小。这些发现表明 RARRES1 是一种真正的肿瘤抑制基因，缺失可促进细胞存活，并减少 B 细胞分化，具有 B 细胞自主和非自主功能。
