Toll-like receptor 4 is a master regulator for colorectal cancer growth under high-fat diet by programming cancer metabolism

Xianjing Hu, Sarwat Fatima, Minting Chen, Keyang Xu, Chunhua Huang, Rui Hong Gong, Tao Su, Hoi Leong Xavier Wong, Zhaoxiang Bian*, Hiu Yee Kwan*

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

11 Citations (Scopus)


Although high-fat diet (HFD) has been implicated in the development of colorectal cancer (CRC), the critical signaling molecule that mediates the cancer growth is not well-defined. Identifying the master regulator that controls CRC growth under HFD can facilitate the development of effective therapeutics for the cancer treatment. In this study, the global lipidomics and RNA sequencing data show that, in the tumor tissues of CRC-bearing mouse models, HFD not only increases tumor weight, but also the palmitic acid level and TLR4 expression, which are reduced when HFD is replaced by control diet. These concomitant changes suggest the roles of palmitic acid and TLR4 in CRC growth. Subsequent studies show that palmitic acid regulates TLR4 expression in PU.1-dependent manner. Knockdown of PU.1 or mutations of PU.1-binding site on TLR4 promoter abolish the palmitic acid-increased TLR4 expression. The role of palmitic acid/PU.1/TLR4 axis in CRC growth is further examined in cell model and animal models that are fed either HFD or palmitic acid-rich diet. More importantly, iTRAQ proteomics data show that knockdown of TLR4 changes the metabolic enzyme profiles in the tumor tissues, which completely abolish the HFD-enhanced ATP production and cancer growth. Our data clearly demonstrate that TLR4 is a master regulator for CRC growth under HFD by programming cancer metabolism.

Original languageEnglish
Article number791
Number of pages13
JournalCell Death and Disease
Issue number8
Publication statusPublished - 12 Aug 2021

Scopus Subject Areas

  • Cellular and Molecular Neuroscience
  • Cancer Research
  • Cell Biology
  • Immunology

User-Defined Keywords

  • Animals
  • Binding Sites
  • Body Weight
  • Cell Line, Tumor
  • Cell Proliferation
  • Colorectal Neoplasms/genetics
  • Diet, High-Fat
  • Disease Models, Animal
  • Feeding Behavior
  • Humans
  • Lymphocytes, Tumor-Infiltrating
  • Male
  • Membrane Glycoproteins/metabolism
  • Mice, Inbred BALB C
  • Myeloid Differentiation Factor 88/metabolism
  • Palmitic Acid/toxicity
  • Principal Component Analysis
  • Promoter Regions, Genetic/genetics
  • Proto-Oncogene Proteins/metabolism
  • Receptors, Interleukin-1/metabolism
  • Toll-Like Receptor 4/genetics
  • Trans-Activators/metabolism


Dive into the research topics of 'Toll-like receptor 4 is a master regulator for colorectal cancer growth under high-fat diet by programming cancer metabolism'. Together they form a unique fingerprint.

Cite this