It is shown that HSPD1 depletion in MYCN-amplified NB cells led to reduced mitochondrial translation, MYCN expression, and tumorigenesis in vitro and in vivo and establishes HSPD1 as a promising target for the treatment of MYCN-amplified NB.
Abstract
MYCN amplification is associated with poor outcomes in neuroblastoma (NB). MYCN encodes a transcription factor that induces the expression of mitochondrial one-carbon enzymes and chaperones, promoting metabolic reprogramming and aggressiveness in NB tumor cells. While the contribution of MYCN to changes in the mitochondrial proteome is well established, how mitochondrial proteostasis contributes to MYCN activity remains poorly understood. Mitochondrial HSP60 (HSPD1) is a conserved mitochondrial chaperone promoting the mitochondrial one-carbon pathway and mitochondrial translation by folding the one-carbon enzyme MTHFD2 and preventing aggregation of mitochondrial ribosomal proteins. Here, we show that HSPD1 depletion in MYCN-amplified NB cells led to reduced mitochondrial translation, MYCN expression, and tumorigenesis in vitro and in vivo. In addition, HSPD1 mRNA and protein correlate with MYCN expression in NB tumors. These results establish HSPD1 as a promising target for the treatment of MYCN-amplified NB.
Direct targeting of the oncoprotein MYC has not yet been successful. We here report a novel dual protein degrader, GT19630, which binds directly to MYC and G1 to S phase transition protein 1 (GSPT1). GT19630 disrupts a novel feedforward loop of MYC and GSPT1, where MYC promotes transcription of GSPT1, and GSPT1 senses...
Yuki Nishida, Valeria Impedovo, Edward Ayoub et al.· Blood· 0 citations
Multiple myeloma (MM) remains largely incurable because of its complex biology and frequent disease relapse. Metabolic reprogramming is increasingly recognized as a critical contributor to MM progression. NAD (P)-dependent steroid dehydrogenase-like protein (NSDHL) has been highlighted as an unfavorable metabolism-rela...
Can Yue, Bei-Hui Huang, Lin Qi et al.· International Journal of Mol...· 0 citations
Benign prostatic hyperplasia (BPH) is a highly prevalent, age-related disorder in men, defined by nonmalignant enlargement of the prostate, which results in bothersome lower urinary tract symptoms and impaired quality of life. Heat shock protein family A member 1 A (HSPA1A)/HSP70, as a molecular chaperone, plays a cr...
Huan Liu, Ji-Zhang Qiu, Huan Lai et al.· Cell Death & Disease· 0 citations
BACKGROUND
HSP90AA1 functions as a molecular chaperone involved in stabilizing multiple oncogenic clients. Its role in endometrial cancer (EC), particularly regarding autophagy regulation, remains unclear.
METHODS
HSP90AA1 expression was examined using UALCAN and Human Protein Atlas (HPA) databases, followed by immun...
L. Xue, Peng-Fei Wang, Chenlingzi Huang et al.· Cellular Signalling· 0 citations
Histone lactylation is an epigenetic modification that connects lactate metabolism with protein function. Our study identified lactate enhances the protein lactylation level not only in Myeloid-derived suppressor cells (MDSCs) of tumor-bearing mice, but also in the tumor tissues of lung cancer patients. This modificati...
Yao Dai, Hai-Yan Dai, Ya-Hui Wang et al.· Cancer immunology research· 0 citations
Acute myeloid leukemia (AML) cells rely heavily on mitochondrial oxidative phosphorylation (OXPHOS) for energy, making mitochondrial function a promising therapeutic target. TCF12, a transcription factor belonging to the basic helix-loop-helix (bHLH) family, has been implicated in various cancers and is highly expresse...
A new machine-learning framework aims to improve the success rate of computational protein design while moving away from results that reproduce sequences found in nature.
