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

Inhibition of the RAF-MEK1/2-ERK signaling pathway is an ideal strategy for treating cancers with NRAS or BRAF mutations. However, the development of resistance due to incomplete inhibition of the pathway and activation of compensatory cell proliferation pathways is a major impediment of the targete...

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Bibliographic Details
Published in:Cells (Basel, Switzerland) Switzerland), 2021-05, Vol.10 (5), p.1101
Main Authors: Ha, Soon-Duck, Lewin, Naomi, Li, Shawn S. C., Kim, Sung-Ouk
Format: Article
Language:English
Subjects:
AKT
AKT protein
Anthrax lethal toxin
Antibodies
Antigens
Cell activation
Cell culture
Cell cycle
Cell proliferation
DESC1
Expression vectors
Fluorides
Gene expression
Genomics
Histone deacetylase
HT-29 cells
Kinases
lethal toxin
Medical prognosis
Melanoma
Mutation
Phosphatase
Phospholipase C
PI-PLC
Plasmids
PLCB1
Raf protein
Signal transduction
Squamous cell carcinoma
Tumor cells
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Summary:Inhibition of the RAF-MEK1/2-ERK signaling pathway is an ideal strategy for treating cancers with NRAS or BRAF mutations. However, the development of resistance due to incomplete inhibition of the pathway and activation of compensatory cell proliferation pathways is a major impediment of the targeted therapy. The anthrax lethal toxin (LT), which cleaves and inactivates MEKs, is a modifiable biomolecule that can be delivered selectively to tumor cells and potently kills various tumor cells. However, resistance to LT and the mechanism involved are yet to be explored. Here, we show that LT, through inhibiting MEK1/2-ERK activation, inhibits the proliferation of cancer cells with NRAS/BRAF mutations. Among them, the human colorectal tumor HT-29 and murine melanoma B16-BL6 cells developed resistance to LT in 2 to 3 days of treatment. These resistant cells activated AKT through a histone deacetylase (HDAC) 8-dependent pathway. Using an Affymetrix microarray, followed by qPCR validation, we identified that the differential expression of the phospholipase C-β1 (PLCB1) and squamous cell carcinoma-1 (DESC1) played an important role in HDAC8-mediated AKT activation and resistance to MEK1/2-ERK inhibition. By using inhibitors, small interference RNAs and/or expression vectors, we found that the inhibition of HDAC8 suppressed PLCB1 expression and induced DESC1 expression in the resistant cells, which led to the inhibition of AKT and re-sensitization to LT and MEK1/2 inhibition. These results suggest that targeting PLCB1 and DESC1 is a novel strategy for inhibiting the resistance to MEK1/2 inhibition.
ISSN:2073-4409
2073-4409
DOI:10.3390/cells10051101