Liu Wenjing, Ni Yueli, Bai Honggang, Liu Xiangjie, Shahzad Asif, Cui Kun, Duan Qiuxin, Bai Ziyuan, Dong Yurong, Yi Zihan, Sai Buqing, Kuang Yingmin, Guo Chen, Zhu Yuechun, Zhang Qiao, Yang Zhe
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Yunnan, Kunming, PR China.
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Yunnan, Kunming, PR China; Department of Clinical Laboratory, The Second Hospital of Jingzhou, Jingzhou, Hubei, PR China.
J Biol Chem. 2025 Mar;301(3):108247. doi: 10.1016/j.jbc.2025.108247. Epub 2025 Jan 31.
Clear cell renal cell carcinoma (ccRCC) is a disease rooted in metabolic disorders, distinguished by abnormally high activity of glucose 6-phosphate dehydrogenase (G6PD). G6PD serves as a key rate-limiting enzyme in the pentose phosphate pathway. Meanwhile, BRAF-activated noncoding RNA (BANCR) has emerged as a crucial regulatory factor linked to various cancers. The expression pattern of BANCR varies across different cancer types, exhibiting apparent duality in its function. However, the precise role and underlying mechanisms of BANCR in ccRCC tumorigenesis remain incompletely understood. Our study indicated that BANCR was downregulated in ccRCC and influenced cell survival by modulating cell proliferation, apoptosis, and G6PD enzyme activity. The underlying mechanism was that BANCR could directly bind to G6PD through a long noncoding RNA-protein interaction, ultimately inhibiting G6PD activity by impeding its dimer formation. Moreover, BANCR exhibited the capability to modulate the glucose metabolic flow in ccRCC cells. Subsequent experiments demonstrated a significant inhibition of tumor growth in vivo upon overexpression of BANCR, and G6PD played a pivotal role in mediating the tumor-suppressive effect of BANCR in ccRCC cells. In conclusion, this study provides novel insights into the molecular pathogenesis of ccRCC, highlights a distinct and new regulatory mechanism responsible for the ectopic overactivation of G6PD in ccRCC progression, and suggests that BANCR-mediated suppression of G6PD activity could emerge as a potential therapeutic strategy for ccRCC treatment.
透明细胞肾细胞癌（ccRCC）是一种源于代谢紊乱的疾病，其特征是葡萄糖-6-磷酸脱氢酶（G6PD）活性异常升高。G6PD是磷酸戊糖途径中的关键限速酶。同时，BRAF激活的非编码RNA（BANCR）已成为与多种癌症相关的关键调节因子。BANCR的表达模式在不同癌症类型中有所不同，其功能表现出明显的双重性。然而，BANCR在ccRCC肿瘤发生中的精确作用和潜在机制仍不完全清楚。我们的研究表明，BANCR在ccRCC中表达下调，并通过调节细胞增殖、凋亡和G6PD酶活性影响细胞存活。潜在机制是BANCR可通过长链非编码RNA-蛋白质相互作用直接与G6PD结合，最终通过阻碍其二聚体形成来抑制G6PD活性。此外，BANCR具有调节ccRCC细胞中葡萄糖代谢流的能力。随后的实验表明，在体内过表达BANCR可显著抑制肿瘤生长，并且G6PD在介导BANCR对ccRCC细胞的肿瘤抑制作用中起关键作用。总之，本研究为ccRCC的分子发病机制提供了新的见解，突出了一种独特的新调节机制，该机制导致ccRCC进展过程中G6PD的异位过度激活，并表明BANCR介导的G6PD活性抑制可能成为ccRCC治疗的潜在策略。
