Histone deacetylase inhibitors induce apoptosis in myeloid leukemia by suppressing autophagy

Area of Science:

• Oncology
• Molecular Biology
• Cellular Biology

Background:

• Histone deacetylase inhibitors (HDACis) are established anti-cancer agents.
• The precise mechanism of HDACi selectivity against malignant versus normal cells remains unclear.
• Gene expression analysis identified HDACis as potent against Down syndrome-associated myeloid leukemia (DS-AMKL).

Purpose of the Study:

• To investigate the antileukemic mechanisms of HDAC inhibitors.
• To elucidate the role of autophagy in HDACi-mediated cancer cell killing.
• To explore the potential of targeting autophagy for cancer therapy.

Main Methods:

• Gene expression-based chemical genomics screening.
• Analysis of autophagy-related protein regulation (e.g., ATG7) by HDACis.
• Assessment of cellular responses to HDAC inhibition, including mitochondrial accumulation, reactive oxygen species production, DNA damage, and apoptosis.

Main Results:

• HDAC inhibitors suppress autophagy by regulating key autophagic proteins like ATG7.
• DS-AMKL cells exhibit low baseline autophagy due to mammalian target of rapamycin (mTOR) activation.
• HDAC inhibition further reduces autophagy below a critical threshold, inducing apoptosis.
• These effects are reversible with autophagy activation and exacerbated by further inhibition.
• The findings extend to other acute myeloid leukemia subgroups with low basal autophagy.

Conclusions:

• Constitutive suppression of autophagy via mTOR activation is an inherent difference between cancer and normal cells.
• HDAC inhibitors exploit this difference by suppressing autophagy, thereby eliminating a pro-survival mechanism in cancer cells.
• This represents a promising strategy for the selective targeting of cancer cells.