Nucleolar HEAT Repeat Containing 1 Up-regulated by the Mechanistic Target of Rapamycin Complex 1 Signaling Promotes Hepatocellular Carcinoma Growth by Dominating Ribosome Biogenesis and Proteome Homeostasis

Yang, Xiaomei; Wang, Xiaoqi; Hu, Li-Peng; Feng, Min; Zhou, Yaoqi; Li, Dongxue; Li, Jun; Miao, Xiao-Cao; Yao, Lishuang; Nie, Hui; Huang, Shan; Xia, Qiang; Zhang, Xueli; Jiang, Shu‐Heng; Zhang, Z.

doi:10.1053/j.gastro.2023.05.029

Cited by 5 publications

(2 citation statements)

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“…The histone chaperon NPM1 has also been shown to bind MYC and be required for its nucleolar localisation and activation of rDNA transcription in p53 mutant mouse embryonic fibroblasts (Li and Hann, 2013 ). Of note, while our work was in revision, HEATR1 was published to be upregulated by the Target of Rapamycin Complex 1 signalling and promote hepatocellular carcinoma (HCC) development (Yang et al, 2023 ). HEATR1 was shown to bind rRNA and its inhibition to disrupt ribogenesis and growth of HCC cells while limited effects were observed in proliferation of immortalized normal hepatic cells.…”

Section: Discussionmentioning

confidence: 99%

“…The divergence may reflect the difference in tumours and models. Yang et al propose that HEATR1 inhibition increases nuclear proteasome activity resulting in reduced nucleolar NPM1 and subsequently preventing Myc nuclear localisation (Yang et al, 2023 ). In GBM cells, despite nucleolar stress induced by HEATR1 depletion, we detect no significant changes in NPM1 protein levels but observe a marked reduction in the ratio of nucleolar to nuclear MYC localisation.…”

Section: Discussionmentioning

confidence: 99%

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Ribogenesis boosts controlled by HEATR1-MYC interplay promote transition into brain tumour growth

Diaz,

Gil-Ranedo,

Jaworek

et al. 2024

EMBO Rep

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Cell commitment to tumourigenesis and the onset of uncontrolled growth are critical determinants in cancer development but the early events directing tumour initiating cell (TIC) fate remain unclear. We reveal a single-cell transcriptome profile of brain TICs transitioning into tumour growth using the brain tumour (brat) neural stem cell-based Drosophila model. Prominent changes in metabolic and proteostasis-associated processes including ribogenesis are identified. Increased ribogenesis is a known cell adaptation in established tumours. Here we propose that brain TICs boost ribogenesis prior to tumour growth. In brat-deficient TICs, we show that this dramatic change is mediated by upregulated HEAT-Repeat Containing 1 (HEATR1) to promote ribosomal RNA generation, TIC enlargement and onset of overgrowth. High HEATR1 expression correlates with poor glioma patient survival and patient-derived glioblastoma stem cells rely on HEATR1 for enhanced ribogenesis and tumourigenic potential. Finally, we show that HEATR1 binds the master growth regulator MYC, promotes its nucleolar localisation and appears required for MYC-driven ribogenesis, suggesting a mechanism co-opted in ribogenesis reprogramming during early brain TIC development.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%