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HDAC8 Activates AKT through Upregulating PLCB1 and Suppressing DESC1 Expression in MEK1/2 Inhibition-Resistant Cells

Soon-Duck Ha1,2, Naomi Lewin1, Shawn S C Li2

  • 1Department of Microbiology & Immunology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, ON N6G 2V4, Canada.

Cells
|June 2, 2021
PubMed

Insights

Targeting the RAF-MEK1/2-ERK pathway is crucial for cancer treatment. This study reveals that resistance to anthrax lethal toxin (LT) involves HDAC8-mediated AKT activation, suggesting PLCB1 and DESC1 as novel targets to overcome resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Targeting the RAF-MEK1/2-ERK pathway is a key strategy for cancers with NRAS or BRAF mutations.
  • Resistance to targeted therapy, often due to pathway reactivation, limits treatment efficacy.
  • Anthrax lethal toxin (LT) inhibits MEK, offering a potent anti-cancer approach, but resistance mechanisms are unknown.

Purpose of the Study:

  • To investigate the mechanisms of resistance to anthrax lethal toxin (LT) in cancer cells.
  • To identify molecular targets for overcoming LT resistance and enhancing MEK1/2-ERK pathway inhibition.
  • To explore the role of histone deacetylase 8 (HDAC8) in LT resistance.

Main Methods:

  • Utilized human colorectal (HT-29) and murine melanoma (B16-BL6) cancer cell lines.
  • Administered anthrax lethal toxin (LT) and MEK1/2-ERK pathway inhibitors.
  • Employed Affymetrix microarray and quantitative PCR (qPCR) for gene expression analysis.
  • Used small interference RNAs (siRNAs), inhibitors, and expression vectors to manipulate gene function.

Main Results:

  • LT effectively inhibited NRAS/BRAF-mutated cancer cell proliferation but resistance emerged within 2-3 days.
  • Resistant cells exhibited AKT activation dependent on histone deacetylase 8 (HDAC8).
  • Differential expression of phospholipase C-β1 (PLCB1) and DESC1 was identified as crucial for HDAC8-mediated AKT activation and LT resistance.
  • Inhibition of HDAC8 reversed resistance by suppressing PLCB1, inducing DESC1, inhibiting AKT, and re-sensitizing cells to LT and MEK1/2 inhibition.

Conclusions:

  • HDAC8-mediated activation of AKT via PLCB1 and DESC1 is a key mechanism of resistance to MEK1/2-ERK pathway inhibition.
  • Targeting PLCB1 and DESC1 represents a novel therapeutic strategy to overcome resistance to MEK inhibitors in cancer treatment.
  • Combined inhibition of MEK and targeting PLCB1/DESC1 may enhance anti-cancer efficacy.
Keywords:
AKTDESC1HT-29 cellsPI-PLCPLCB1cancerlethal toxinresistance

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