JoVE - Journal of Visualized Experiments
JoVE Visualize
Contact Us

ZMIZ1 lactylation induces tamoxifen resistance in breast cancer through increasing transcriptional activity of Nanog to impact cell stemness and cholesterol uptake

  • 0Breast cancer Diagnosis and Treatment Center, Harbin Medical University Cancer Hospital, Harbin, China.
Cell Biology and Toxicology +

|

July 16, 2025

|

July 16, 2025

View abstract on PubMed

Summary

This summary is machine-generated.

Tamoxifen resistance in breast cancer is linked to metabolic reprogramming. Lactic acid promotes ZMIZ1 protein stability, increasing stemness and cholesterol accumulation, offering new therapeutic targets.

Area Of Science

  • Oncology
  • Metabolic pathways
  • Molecular biology

Background

  • Tamoxifen is a key treatment for oestrogen receptor (ER)-positive breast cancer (BC).
  • Acquired Tamoxifen resistance is a major clinical challenge in BC treatment.
  • Understanding resistance mechanisms is crucial for improving patient outcomes.

Purpose Of The Study

  • To investigate the biological processes and metabolic alterations in Tamoxifen-resistant breast cancer.
  • To identify key molecular players and pathways driving Tamoxifen resistance.
  • To explore the link between metabolic reprogramming and cancer stemness.

Main Methods

  • Bioinformatics analysis of gene expression in Tamoxifen-resistant cells.
  • Metabolomics profiling to identify altered metabolites.
  • In vitro (cell viability, proliferation, invasion, colony formation) and in vivo (tumour growth) assays to evaluate resistance.
  • Analysis of protein modifications (lactylation, SUMOylation, ubiquitination) and protein-protein interactions.

Main Results

  • Tamoxifen-resistant BC exhibits metabolic reprogramming towards glycolysis.
  • Lactic acid promotes ZMIZ1 lactylation, increasing its stability by inhibiting SUMOylation and ubiquitination.
  • Elevated ZMIZ1 enhances Nanog transcriptional activity, leading to increased stemness and cholesterol accumulation.
  • ZMIZ1 knockdown reduces Tamoxifen resistance, an effect reversed by Nanog overexpression.

Conclusions

  • A novel mechanism for Tamoxifen resistance involving the ZMIZ1/Nanog/NPC2 axis is identified.
  • This study reveals a connection between glucose glycolysis and cholesterol metabolism in Tamoxifen-resistant BC.
  • Targeting ZMIZ1 or related pathways may offer new strategies to overcome Tamoxifen resistance.

Keywords:

Related Concept Videos

Abnormal Proliferation 02:23

4.6K

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...

lncRNA - Long Non-coding RNAs 02:39

9.0K

In humans, more than 80% of the genome gets transcribed. However, only around 2% of the genome codes for proteins. The remaining part produces non-coding RNAs which includes ribosomal RNAs, transfer RNAs, telomerase RNAs, and regulatory RNAs, among other types. A large number of regulatory non-coding RNAs have been classified into two groups depending upon their length – small non-coding RNAs, such as microRNA, which are less than 200 nucleotides in length, and long non-coding RNA...

MicroRNAs 01:22

3.1K

MicroRNA (miRNA) are short, regulatory RNA transcribed from introns (non-coding regions of a gene) or intergenic regions (stretches of DNA present between genes). Several processing steps are required to form biologically active, mature miRNA. The initial transcript, called primary miRNA (pri-mRNA), base-pairs with itself, forming a stem-loop structure. Within the nucleus, an endonuclease enzyme, called Drosha, shortens the stem-loop structure into hairpin-shaped pre-miRNA. After the pre-miRNA...

Epigenetic Regulation 01:37

3.1K

Epigenetic changes alter the physical structure of the DNA without changing the genetic sequence and often regulate whether genes are turned on or off. This regulation ensures that each cell produces only proteins necessary for its function. For example, proteins that promote bone growth are not produced in muscle cells. Epigenetic mechanisms play an essential role in healthy development. Conversely, precisely regulated epigenetic mechanisms are disrupted in diseases like cancer.
X-chromosome...

Loss of Tumor Suppressor Gene Functions 01:12

5.1K

Tumor suppressor genes are normal genes that can slow down cell division, repair DNA mistakes, or program the cells for apoptosis in case of irreparable damage. Hence, they play an essential role in preventing the proliferation of damaged cells.
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...

mTOR Signaling and Cancer Progression 03:03

3.9K

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...