Valproic acid attenuates skeletal muscle wasting by inhibiting C/EBPβ-regulated atrogin1 expression in cancer cachexia

Am J Physiol Cell Physiol. 2016 Jul 1;311(1):C101-15. doi: 10.1152/ajpcell.00344.2015. Epub 2016 Apr 27.


Muscle wasting is the hallmark of cancer cachexia and is associated with poor quality of life and increased mortality. Valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, has important biological effects in the treatment of muscular dystrophy. To verify whether VPA could ameliorate muscle wasting induced by cancer cachexia, we explored the role of VPA in two cancer cachectic mouse models [induced by colon-26 (C26) adenocarcinoma or Lewis lung carcinoma (LLC)] and atrophied C2C12 myotubes [induced by C26 cell conditioned medium (CCM) or LLC cell conditioned medium (LCM)]. Our data demonstrated that treatment with VPA increased the mass and cross-sectional area of skeletal muscles in tumor-bearing mice. Furthermore, treatment with VPA also increased the diameter of myotubes cultured in conditioned medium. The skeletal muscles in cachectic mice or atrophied myotubes treated with VPA exhibited reduced levels of CCAAT/enhancer binding protein beta (C/EBPβ), resulting in atrogin1 downregulation and the eventual alleviation of muscle wasting and myotube atrophy. Moreover, atrogin1 promoter activity in myotubes was stimulated by CCM via activating the C/EBPβ-responsive cis-element and subsequently inhibited by VPA. In contrast to the effect of VPA on the levels of C/EBPβ, the levels of inactivating forkhead box O3 (FoxO3a) were unaffected. In summary, VPA attenuated muscle wasting and myotube atrophy and reduced C/EBPβ binding to atrogin1 promoter locus in the myotubes. Our discoveries indicate that HDAC inhibition by VPA might be a promising new approach for the preservation of skeletal muscle in cancer cachexia.

Keywords: C/EBPβ; VPA; atrogin1; cancer cachexia; muscle wasting.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / complications
  • Adenocarcinoma / drug therapy*
  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology
  • Animals
  • Binding Sites
  • CCAAT-Enhancer-Binding Protein-beta / genetics
  • CCAAT-Enhancer-Binding Protein-beta / metabolism*
  • Cachexia / etiology
  • Cachexia / metabolism
  • Cachexia / pathology
  • Cachexia / prevention & control*
  • Carcinoma, Lewis Lung / complications
  • Carcinoma, Lewis Lung / drug therapy*
  • Carcinoma, Lewis Lung / metabolism
  • Carcinoma, Lewis Lung / pathology
  • Cell Line, Tumor
  • Colonic Neoplasms / complications
  • Colonic Neoplasms / drug therapy*
  • Colonic Neoplasms / metabolism
  • Colonic Neoplasms / pathology
  • Culture Media, Conditioned / metabolism
  • Dose-Response Relationship, Drug
  • Down-Regulation
  • Female
  • Histone Deacetylase Inhibitors / pharmacology*
  • Male
  • Mice, Inbred C57BL
  • Muscle Fibers, Skeletal / drug effects
  • Muscle Fibers, Skeletal / metabolism
  • Muscle Fibers, Skeletal / pathology
  • Muscle Proteins / genetics
  • Muscle Proteins / metabolism*
  • Muscle, Skeletal / drug effects*
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / pathology
  • Muscular Atrophy / etiology
  • Muscular Atrophy / metabolism
  • Muscular Atrophy / pathology
  • Muscular Atrophy / prevention & control*
  • Promoter Regions, Genetic
  • Proteolysis
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • SKP Cullin F-Box Protein Ligases / genetics
  • SKP Cullin F-Box Protein Ligases / metabolism*
  • Signal Transduction / drug effects
  • Time Factors
  • Valproic Acid / pharmacology*


  • CCAAT-Enhancer-Binding Protein-beta
  • Cebpb protein, mouse
  • Culture Media, Conditioned
  • Histone Deacetylase Inhibitors
  • Muscle Proteins
  • RNA, Messenger
  • Valproic Acid
  • Fbxo32 protein, mouse
  • SKP Cullin F-Box Protein Ligases