ArticleCancer & metabolism2021
Tumor suppressor SMAR1 regulates PKM alternative splicing by HDAC6-mediated deacetylation of PTBP1.
Article in Cancer & metabolism, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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21 citing papers in PubMed, 39 citations in OpenAlex.
- Splicing genes as main targets of differential splicing.G3 (Bethesda, Md.) · 2026Article
- In vivo CRISPR screening links NFKB1 to endocrine resistance in ER+ breast cancer.Endocrine-related cancer · 2026Article
- Lactylation of PTBP1 drives a pro-apoptotic positive feedback loop in microglia following oxygen-glucose deprivation/reoxygenation-induced injury.Cell death & disease · 2026Article
- Exploring the role of protein homeostasis regulation in glycolysis in head and neck tumors.Human cell · 2026Review
- Oncogenic functions of polypyrimidine tract-binding protein 1 in breast cancer metabolism and progression.Biochemistry and biophysics reports · 2026Article
- KAT5 promotes tumor growth in androgen-independent prostate cancer by facilitating aerobic glycolysis.Translational oncology · 2025Article
- Splicing factor PTBP1 promotes hepatocarcinogenesis via oncogenic splice-switching of MAPT.Oncology research · 2025Article
- PTBP1 crotonylation promotes colorectal cancer progression through alternative splicing-mediated upregulation of the PKM2 gene.Journal of translational medicine · 2024Article
- The Regulatory Network of hnRNPs Underlying RegulatingBiomolecules · 2024Review
- ZNF471 Interacts with BANP to Reduce Tumour Malignancy by Inactivating PI3K/AKT/mTOR Signalling but is Frequently Silenced by Aberrant Promoter Methylation in Renal Cell Carcinoma.International journal of biological sciences · 2024Article
- Review of cancer cell volatile organic compounds: their metabolism and evolution.Frontiers in molecular biosciences · 2024Review
- A novel LINC00478 serves as a tumor suppressor in endometrial carcinoma progression.Journal of cancer research and clinical oncology · 2023Article
- LncRNA CCAT1 facilitates the progression of gastric cancer via PTBP1-mediated glycolysis enhancement.Journal of experimental & clinical cancer research : CR · 2023Article
- SL-scan identifies synthetic lethal interactions in cancer using metabolic networks.Scientific reports · 2023Article
- PTBP1 drives c-Myc-dependent gastric cancer progression and stemness.British journal of cancer · 2023Article
- The physiology of alternative splicing.Nature reviews. Molecular cell biology · 2023Review
- RBX1 regulates PKM alternative splicing to facilitate anaplastic thyroid carcinoma metastasis and aerobic glycolysis by destroying the SMAR1/HDAC6 complex.Cell & bioscience · 2023Article
- SMAR1 inhibits proliferation, EMT and Warburg effect of bladder cancer cells by suppressing the activity of the Wnt/β-catenin signaling pathway.Cell cycle (Georgetown, Tex.) · 2023Article
- Proteomic analysis of holocarboxylase synthetase deficient-MDA-MB-231 breast cancer cells revealed the biochemical changes associated with cell death, impaired growth signaling, and metabolism.Frontiers in molecular biosciences · 2023Article
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10 authors at 2 institutions in 1 country.
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Abstract
backgroundHighly proliferating cancer cells exhibit the Warburg effect by regulation of PKM alternative splicing and promoting the expression of PKM2. Majority of the alternative splicing events are known to occur in the nuclear matrix where various MARBPs actively participate in the alternative splicing events. SMAR1, being a MARBP and an important tumor suppressor, is known to regulate the splicing of various cancer-associated genes. This study focuses on the regulation of PKM alternative splicing and inhibition of the Warburg effect by SMAR1.
methodsImmunohistochemistry was performed in breast cancer patient samples to establish the correlation between SMAR1 and PKM isoform expression. Further, expression of PKM isoforms upon modulation in SMAR1 expression in breast cancer cell lines was quantified by qRT-PCR and western blot. The acetylation status of PTBP1 was estimated by immunoprecipitation along with its enrichment on PKM pre-mRNA by CLIP in SMAR1 knockdown conditions. The role of SMAR1 in tumor metabolism and tumorigenesis was explored by in vitro enzymatic assays and functional assays upon SMAR1 knockdown. Besides, in vivo tumor formation by injecting adeno-SMAR1-transduced MDA-MB-231 cells in NOD/SCID mice was performed.
resultsThe expression profile of SMAR1 and PKM isoforms in breast cancer patients revealed that SMAR1 has an inverse correlation with PKM2 and a positive correlation with PKM1. Further quantitative PKM isoform expression upon modulation in SMAR1 expression also reflects that SMAR1 promotes the expression of PKM1 over tumorigenic isoform PKM2. SMAR1 deacetylates PTBP1 via recruitment of HDAC6 resulting in reduced enrichment of PTBP1 on PKM pre-mRNA. SMAR1 inhibits the Warburg effect, tumorigenic potential of cancer cells, and in vivo tumor generation in a PKM2-dependent manner.
conclusionsSMAR1 regulates PKM alternative splicing by causing HDAC6-dependent deacetylation of PTBP1, resulting in reduced enrichment of PTBP1 on PKM pre-mRNA. Additionally, SMAR1 suppresses glucose utilization and lactate production via repression of PKM2 expression. This suggests that tumor suppressor SMAR1 inhibits tumor cell metabolism and tumorigenic properties of cancer cells via regulation of PKM alternative splicing.
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