Kohno Susumu, Okahashi Nobuyuki, Wan Yuansong, Yu Hai, Takegami Yujiro, Linn Paing, Nagatani Naoko, Kitajima Shunsuke, Kawada Teruo, Matsuda Fumio, Shimizu Hiroshi, Takahashi Chiaki
Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, Japan.
Graduate School of Information Science and Technology, Osaka University, Suita, Osaka, Japan.
Cell Death Dis. 2025 Jul 24;16(1):559. doi: 10.1038/s41419-025-07850-3.
Most glycolytic enzymes are transcriptionally controlled by hypoxia-inducible factor-1α (HIF-1α) and/or MYC, however, phosphoglycerate mutases (PGAMs) are exceptional. Retinoblastoma tumor suppressor 1 (RB1) loss converts poorly spherogenic Trp53-null leiomyosarcoma cells to highly spherogenic. We determined a gene expression signature of RB1 loss-of-function in this setting and identified PGAM2 as a positive transcriptional target of RB1. Later, we found that RB1 positively controls PGAM1 as well in different tissues. RB1 deficiency induced a metabolic shift in the glycolytic pathway in a manner compatible with PGAM downregulation. Many of the metabolic features induced by RB1 loss were antagonized by PGAM overexpression. Furthermore, differentiation deficiency following RB1 loss was rescued by PGAM overexpression or pyruvate supplementation to varied degrees. These findings suggest that the RB1-PGAM1/2 axis at least partially controls RB1-dependent differentiation.
大多数糖酵解酶受缺氧诱导因子-1α（HIF-1α）和/或MYC的转录调控，然而，磷酸甘油酸变位酶（PGAMs）却是个例外。视网膜母细胞瘤肿瘤抑制因子1（RB1）的缺失可将致球能力差的Trp53基因缺失的平滑肌肉瘤细胞转变为高致球能力的细胞。我们确定了在此情况下RB1功能丧失的基因表达特征，并将PGAM2鉴定为RB1的一个正向转录靶点。后来，我们发现RB1在不同组织中也正向调控PGAM1。RB1缺乏以与PGAM下调相一致的方式诱导糖酵解途径中的代谢转变。RB1缺失诱导的许多代谢特征被PGAM过表达所拮抗。此外，RB1缺失后的分化缺陷通过PGAM过表达或丙酮酸补充在不同程度上得到挽救。这些发现表明，RB1-PGAM1/2轴至少部分控制RB1依赖的分化。
