Although glycolysis plays a pivotal role in breast cancer stem-like cell (BCSC) reprogramming,
the molecular mechanisms that couple glycolysis to cancer stem-like cells remain unclear.
SETD5 is a previously uncharacterized member of the histone lysine methyltransferase family.
The goal of this study was to explore the mechanisms underlying the promotion of stem-like
and glycolysis activation traits by SETD5. Previous studies have shown that overexpression of SETD5 in breast cancer tissues is associated positively with progression. The present study
showed that SETD5 expression was enriched in BCSCs. Down-regulation of SETD5 significantly decreased BCSC properties and glycolysis in vitro and in vivo. Interestingly, SETD5 and glycolytic enzymes were accumulated in the central hypoxic regions of subcutaneous
tumor tissues. Bioinformatic analysis predicted SETD5 binding to E1A binding protein p300 (EP300), and subsequently to hypoxia-inducible
factor 1α (HIF-1α). The mechanistic study found that SETD5 is an upstream effector of EP300/HIF-1α. SETD5 knockdown reduced the expression of HIF-1α, hexokinase-2, and 6-phosphofructo-2-kinase
in the nucleus after treatment with cobalt chloride, a chemical hypoxia mimetic agent
that activates HIF-1α to accumulate in the nucleus. Therefore, SETD5 is required for glycolysis in BCSCs through binding to EP300/HIF-1α and could be
a potential therapeutic target for breast cancer patients.
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to The American Journal of PathologyAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 29 cancer groups, 1990 to 2017.JAMA Oncol. 2019; 5: 1740-1768
- Cancer metabolism: current perspectives and future directions.Cell Death Dis. 2012; 3: e248-e257
- From tumor cell metabolism to tumor immune escape.Int J Biochem Cell Biol. 2013; 45: 106-113
- Cancer stem cell metabolism: a potential target for cancer therapy.Mol Cancer. 2016; 15: 69
- Targeting stem cells-clinical implications for cancer therapy.Curr Stem Cell Res Ther. 2009; 4: 147-153
- Effective elimination of cancer stem cells by a novel drug combination strategy.Stem Cells. 2013; 31: 23-34
- Hypoxia inducible factors in cancer stem cells.Br J Cancer. 2010; 102: 789-795
- A novel miR-155/miR-143 cascade controls glycolysis by regulating hexokinase 2 in breast cancer cells.EMBO J. 2012; 31: 1985-1998
- An inducible gene product for 6-phosphofructo-2-kinase with an AU-rich instability element: role in tumor cell glycolysis and the Warburg effect.Proc Natl Acad Sci U S A. 1999; 96: 3047-3052
- PKM2 promotes tumor angiogenesis by regulating HIF-1α through NF-κB activation.Mol Cancer. 2016; 15: 3-17
- HIF1/2α mediates hypoxia-induced LDHA expression in human pancreatic cancer cells.Oncotarget. 2017; 8: 24840-24852
- Transcriptional/epigenetic regulator CBP/p300 in tumorigenesis: structural and functional versatility in target recognition.Cell Mol Life Sci. 2013; 22: 3989-4008
- Chetomin, targeting HIF-1α/p300 complex, exhibits antitumour activity in multiple myeloma.Br J Cancer. 2016; 114: 519-523
- De novo SETD5 loss-of-function variant as a cause for intellectual disability in a 10-year old boy with an aberrant blind ending bronchus.Am J Med Genet A. 2017; 173: 3165-3171
- SET domains and histone methylation.Curr Opin Struct Biol. 2003; 13: 699-705
- The methyl binding domain 3/nucleosome remodelling and deacetylase complex regulates neural cell fate determination and terminal differentiation in the cerebral cortex.Neural Dev. 2015; 10: 13-32
- Bace1 modulates myelination in the central and peripheral nervous system.Nat Neurosci. 2006; 9: 1520-1525
- SET domain containing protein 5 (SETD5) enhances tumor cell invasion and is associated with a poor prognosis in non-small cell lung cancer patients.BMC Cancer. 2019; 19: 736-745
- SET domain-containing 5 is a potential prognostic biomarker that promotes esophageal squamous cell carcinoma stemness.Exp Cell Res. 2020; 389: 111861
- Genetic alterations of histone lysine methyltransferases and their significance in breast cancer.Oncotarget. 2015; 6: 2466-2482
- Monomethyltransferase SETD8 regulates breast cancer metabolism via stabilizing hypoxia-inducible factor 1α.Cancer Lett. 2017; 390: 1-10
- Gli1, a potential regulator of esophageal cancer stem cell, is identified as an independent adverse prognostic factor in esophageal squamous cell carcinoma.J Cancer Res Clin Oncol. 2017; 143: 243-254
- GLI1 promotes cancer stemness through intracellular signaling pathway PI3K/Akt/NFκB in colorectal adenocarcinoma.Exp Cell Res. 2018; 373: 145-154
- Su(var)3–9, enhancer of zeste, and trithorax domain-containing 5 facilitates tumor growth and pulmonary metastasis through up-regulation of AKT1 signaling in breast cancer.Am J Pathol. 2021; 191: 180-193
- Module map of stem cell genes guides creation of epithelial cancer stem cells.Cell Stem Cell. 2008; 2: 333-344
- Setd5 is essential for mammalian development and the co-transcriptional regulation of histone acetylation.Development. 2016; 143: 4595-4607
- SETD5 regulates chromatin methylation state and preserves global transcriptional fidelity during brain development and neuronal wiring.Neuron. 2019; 104: 271-289.e13
- SIRT3 opposes reprogramming of cancer cell metabolism through HIF-1α destabilization.Cancer Cell. 2011; 19: 416-428
- Hypoxia inducible factor-α binding and ubiquitylation by the von Hippel-Lindau tumor suppressor protein.J Biol Chem. 2000; 275: 25733-25741
- Structural and functional analysis of hypoxia-inducible factor 1.Kidney Int. 1997; 51: 553-555
Article info
Publication history
Published online: January 18, 2022
Accepted:
December 14,
2021
Footnotes
Supported by National Natural Science Foundation of China grant 82160594 (Y.X.).
Z.Y., C.Z., and X.L. are co-first authors.
Disclosures: None declared.
Identification
Copyright
© 2022 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
