bims-merabr Biomed News
on Metabolic rewiring in aggressive breast cancer
Issue of 2024–12–29
six papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center
  1. USP35 promotes breast cancer progression by regulating PFK-1 ubiquitination to mediate glycolysis.
  2. Knockdown of NDUFAF6 inhibits breast cancer progression via promoting mitophagy and apoptosis.
  3. Targeting UBE2T suppresses breast cancer stemness through CBX6-mediated transcriptional repression of SOX2 and NANOG.
  4. RNF123 inhibits cell viability, cell cycle and colony formation of breast cancer by inhibiting glycolysis via ubiquitination of PFKP.
  5. CAPE activates AMPK and Foxo3 signaling to induce growth inhibition and ferroptosis in triple-negative breast cancer.
  6. From ductal carcinoma in situ to invasive breast cancer: the prognostic value of the extracellular microenvironment.
  1. Am J Physiol Cell Physiol. 2024 Dec 23.
    USP35 promotes breast cancer progression by regulating PFK-1 ubiquitination to mediate glycolysis.
    Weibin Lian, Chengye Hong, Debo Chen, Chuan Wang.
      Background: Ubiquitin‑specific protease 35 (USP35) was found to be involved in various tumor progression, but its role in breast cancer remains largely unknown. Methods: USP35 mRNA and protein expression in breast cancer tissues and cells were evaluated by qPCR and Western bolt (WB), respectively. Subsequently, flow cytometry and EDU labeling were used to evaluate breast cancer cell apoptosis and proliferation. Cellular glycolytic function was analyzed using the Seahorse assay and various kits. Furthermore, Co-immunoprecipitation (Co-IP) and immunoprecipitation (IP) assays were utilized to validate the deubiquitylation mechanism of USP35. Finally, a subcutaneous human xenograft tumor model was established in nude mice to verify the effect of USP35 in vivo. Results: By examining the clinical samples and cell lines, we found that USP35 expression was significantly upregulated in breast cancer. Further functional studies showed that knockdown USP35 expression inhibited cell proliferation and promoted apoptosis. In addition, knockdown of USP35 decreased PFK-1 expression and was associated with lower extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) compared with sh-Control. Co-IP assays identified phosphofructokinase1 (PFK-1) as a direct deubiquitiation target of USP35. Importantly, we demonstrated that PFK-1 is an essential mediator for USP35-induced cell proliferation and glycolysis in vitro and in vivo. Conclusion: This study identified that USP35 regulates proliferation and glycolysis of breast cancer cells by mediating the ubiquitination level of PFK-1. The USP35/PFK-1 axis offers novel insight for the treatment of breast cancer.
    Keywords:  Breast cancer; Deubiquitylation; Glycolysis; PFK-1; USP35
    DOI:  https://doi.org/10.1152/ajpcell.00733.2024
  2. Cancer Biol Ther. 2025 Dec;26(1): 2445220
    Knockdown of NDUFAF6 inhibits breast cancer progression via promoting mitophagy and apoptosis.
    Shang Wu, Xindi Ma, Xiangmei Zhang, Kaiye Du, Chao Shi, Ahmed Ali Almaamari, Boye Han, Suwen Su, Yunjiang Liu.
       BACKGROUND: While NDUFAF6 is implicated in breast cancer, its specific role remains unclear.
    METHODS: The expression levels and prognostic significance of NDUFAF6 in breast cancer were assessed using The Cancer Genome Atlas, Gene Expression Omnibus, Kaplan-Meier plotter and cBio-Portal databases. We knocked down NDUFAF6 in breast cancer cells using small interfering RNA and investigated its effects on cell proliferation and migration ability. We performed gene expression analysis and validated key findings using protein analysis. We also assessed mitochondrial activity and cellular metabolism.
    RESULTS: NDUFAF6 was highly expressed in breast cancer, which was associated with a poorer prognosis. Knockdown of NDUFAF6 reduced the proliferation and migration ability of breast cancer cells. Transcriptome analysis revealed 2,101 differentially expressed genes enriched in apoptosis and mitochondrial signaling pathways. Western blot results showed NDUFAF6 knockdown enhanced apoptosis. In addition, differential gene enrichment analysis was related to mitochondrial signaling pathways, and western blot results verified that mitophagy was enhanced in NDUFAF6 knockdown breast cancer cells. JC-1 assay also showed that mitochondrial dysfunction and reactive oxygen species content were increased after knocking down NDUFAF6. In addition, basal and maximal mitochondrial oxygen consumption decreased, and intracellular glycogen content increased.
    CONCLUSIONS: Knockdown of NDUFAF6 resulted in apoptosis and mitophagy in breast cancer cells and NDUFAF6 may be a potential molecular target for breast cancer therapy.
    Keywords:  Breast cancer; NDUFAF6; apoptosis; mitophagy; prognosis
    DOI:  https://doi.org/10.1080/15384047.2024.2445220
  3. Cancer Lett. 2024 Dec 21. pii: S0304-3835(24)00804-8. [Epub ahead of print] 217409
    Targeting UBE2T suppresses breast cancer stemness through CBX6-mediated transcriptional repression of SOX2 and NANOG.
    Keshen Wang, Qichen He, Xiangyan Jiang, Tao Wang, Zhigang Li, Huiguo Qing, Yuman Dong, Yong Ma, Bin Zhao, Junchang Zhang, Haonan Sun, Zongrui Xing, Yuxia Wu, Wenbo Liu, Junhong Guan, Ailin Song, Yan Wang, Peng Zhao, Long Qin, Wengui Shi, Zeyuan Yu, Huinian Zhou, Zuoyi Jiao.
      Breast cancer stem cells (BCSCs) are the main cause of breast cancer recurrence and metastasis. While the ubiquitin-proteasome system contributes to the regulation of BCSC stemness, the underlying mechanisms remain unclear. Here, we identified ubiquitin-conjugating enzyme E2T (UBE2T) as a pivotal ubiquitin enzyme regulating BCSC stemness through systemic screening assays, including single-cell RNA sequencing (scRNA-seq) and stemness-index analysis. We found that patients with high UBE2T expression exhibited worse prognosis than those with low expression (10-year PFS: 55.95% vs. 85.08%), which are consistent across various subtypes of breast cancers. Genetic ablation of UBE2T suppresses BCSC stemness and tumor progression in organoids and spontaneous MMTV-PyMT mice, dependent on the transcriptional inactivation of pluripotency genes SOX2 and NANOG. Mechanically, UBE2T collaborates with the E3 ligase TRIM25 to perform K48-linked polyubiquitination and degradation of CBX6 at K214, which deficiency helps to promote the transcription of SOX2 and NANOG and enhances BCSC stemness. The pharmacological inhibitor of UBE2T significantly reduced the expression of NANOG and SOX2, suppressed tumor progression, and demonstrated synergistic effects when combined with chemotherapeutics, but not with other treatments. Collectively, our study revealed that the UBE2T-TRIM25-CBX6 axis can regulate BCSC stemness and offers a potentially therapeutic strategy to combat breast cancer in a clinical translation setting.
    Keywords:  Breast cancer; CBX6; UBE2T; stemness; ubiquitination
    DOI:  https://doi.org/10.1016/j.canlet.2024.217409
  4. Naunyn Schmiedebergs Arch Pharmacol. 2024 Dec 27.
    RNF123 inhibits cell viability, cell cycle and colony formation of breast cancer by inhibiting glycolysis via ubiquitination of PFKP.
    Xiaoqing Chen, Weijie Su, Jiewen Chen, Peng Ouyang, Jin Gong.
      E3 ubiquitin ligases have the potential to modulate key oncogenic pathways. RING finger protein 123 (RNF123), as an E3 ubiquitin ligase, has been functioned as a tumor suppressor. This study was designed to explore the role of RNF123 in breast cancer. Immunohistochemistry was applied to examine protein expression in breast cancer tissues. Western blot and Quantitative Real-time PCR were performed to gauge protein and mRNA levels. Lentivirus transduction was used to overexpress or silence genes of interest. Cell Counting Kit-8, flow cytometry, and colony formation assays were used to assess cell viability, cell cycle, and colony formation. Extracellular acidification rate, lactic acid and adenosine triphosphate were used for glycolysis assay. Co-immunoprecipitation (Co-IP) and ubiquitination analysis were used to explore the interaction between RNF123 and 6-Phosphofructo-2-kinase (PFKP). In vivo experiments were performed with xenograft tumor models. RNF123 was downregulated in tumor tissues and cells, overexpression of which significantly decreased the viability and colony-forming ability of tumor cells, suppressed the progression of the cell cycle and glycolytic activity, and suppressed tumor growth in vivo. Co-IP and ubiquitination analysis revealed that there was an interaction between RNF123 and PFKP, and RNF123 could induce ubiquitination of PFKP. PFKP could reverse the effects of RNF123 on tumor cells. RNF123 inhibited cell viability, cell cycle and colony formation of breast cancer cells by inhibiting glycolysis via ubiquitination of PFKP.
    Keywords:  Breast cancer; Glycolysis; PFKP; RNF123; Tumor growth; Ubiquitination
    DOI:  https://doi.org/10.1007/s00210-024-03723-2
  5. PLoS One. 2024 ;19(12): e0315037
    CAPE activates AMPK and Foxo3 signaling to induce growth inhibition and ferroptosis in triple-negative breast cancer.
    Qilu Fang, Qichuan Fang, Rui Cheng, Tingting Feng, Wenxiu Xin.
       PURPOSE: Approximately 20% of all breast cancer cases are classified as triple-negative breast cancer (TNBC), which represents the most challenging subtype due to its poor prognosis and high metastatic rate. Caffeic acid phenethyl ester (CAPE), the main component extracted from propolis, has been reported to exhibit anticancer activity across various tumor cell types. This study aimed to investigate the effects and mechanisms of CAPE on TNBC.
    METHODS: MDA-MB-231 and MDA-MB-468 cells were treated with CAPE. CCK8 and colony formation assays were performed to analyze cell proliferation. Western blot, TUNEL and Annexin V-FITC/PI staining methods were employed to assess cell apoptosis. ROS, MDA, SOD, GSH, C11-bodipy staining, along with measurements of GPX4 and Ferritin levels, were utilized for ferroptosis detection. Western blot and immunofluorescence analysis were used to assess key regulatory molecules. The cells were subjected to treatments involving ferroptosis inhibition, AMPK inhibition, or Foxo3 inhibition, followed by CAPE administration to assess cell proliferation, apoptosis, and ferroptosis. Tumor xenografts were used to evaluate the antitumor efficacy of CAPE.
    RESULTS: CAPE not only suppressed cell proliferation but also promoted apoptosis followed by ferroptosis. Co-incubation with Fer-1 (a ferroptosis inhibitor) diminished CAPE's suppressive effects on proliferation and apoptosis induction. CAPE treatment enhanced the phosphorylation of AMPK and promoted the nuclear translocation of Foxo3. Inhibition of both AMPK and Foxo3 by siRNAs or inhibitors (Compc, TIC10) reversed the growth retardation induced by CAPE as well as its pro-apoptotic effects leading to ferroptosis. Specifically, AMPK inhibition abrogated the CAPE-induced nuclear translocation of Foxo3. CAPE significantly inhibited tumor growth in nude mice bearing TNBC xenografts.
    CONCLUSION: CAPE possesses a resistance effect on TNBC via activation of AMPK and Foxo3 signaling pathways.
    DOI:  https://doi.org/10.1371/journal.pone.0315037
  6. J Exp Clin Cancer Res. 2024 Dec 23. 43(1): 329
    From ductal carcinoma in situ to invasive breast cancer: the prognostic value of the extracellular microenvironment.
    Taylor S Hulahan, Peggi M Angel.
      Ductal carcinoma in situ (DCIS) is a noninvasive breast disease that variably progresses to invasive breast cancer (IBC). Given the unpredictability of this progression, most DCIS patients are aggressively managed similar to IBC patients. Undoubtedly, this treatment paradigm places many DCIS patients at risk of overtreatment and its significant consequences. Historically, prognostic modeling has included the assessment of clinicopathological features and genomic markers. Although these provide valuable insights into tumor biology, they remain insufficient to predict which DCIS patients will progress to IBC. Contemporary work has begun to focus on the microenvironment surrounding the ductal cells for molecular patterns that might predict progression. In this review, extracellular microenvironment alterations occurring with the malignant transformation from DCIS to IBC are detailed. Not only do changes in collagen abundance, organization, and localization mediate the transition to IBC, but also the discrete post-translational regulation of collagen fibers is understood to promote invasion. Other extracellular matrix proteins, such as matrix metalloproteases, decorin, and tenascin C, have been characterized for their role in invasive transformation and further demonstrate the prognostic value of the extracellular matrix. Importantly, these extracellular matrix proteins influence immune cells and fibroblasts toward pro-tumorigenic phenotypes. Thus, the progressive changes in the extracellular microenvironment play a key role in invasion and provide promise for prognostic development.
    Keywords:  Biomarker; Collagen; Ductal carcinoma in situ (DCIS); Extracellular matrix (ECM); Glycosylation; Invasive breast cancer (IBC); Proteomics; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s13046-024-03236-z
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