The protein farnesyltransferase regulates HDAC6 activity in a microtubule-dependent manner

Area of Science:

• Cellular biology
• Molecular oncology
• Biochemistry

Background:

• HDAC6 is a cytoplasmic deacetylase regulating cellular processes like stress response, protein folding, and cell migration.
• HDAC6 is a potential target for cancer chemotherapy, but its upstream regulation is not well understood.
• Previous studies implicated HDAC6 as a target for farnesyltransferase inhibitors (FTIs), despite lacking a farnesylation motif.

Purpose of the Study:

• To investigate the upstream regulation of HDAC6 activity.
• To elucidate the relationship between farnesyltransferase (FTase) and HDAC6.
• To determine the role of FTase-microtubule interaction in HDAC6 regulation and its implications for cancer therapy.

Main Methods:

• Co-immunoprecipitation to detect protein complexes in vivo and in vitro.
• Microtubule binding assays to study FTase-microtubule interactions.
• Stable knockdown of FTase alpha subunit (FTalphaKD) and assessment of HDAC6 activity.
• Cell proliferation assays using Taxol and lonafarnib in FTalphaKD cells.

Main Results:

• FTase and HDAC6 form a complex with microtubules.
• FTase binds directly to microtubules via its alpha subunit, requiring the tubulin C terminus.
• FTI treatment or FTalphaKD abrogated HDAC6 activity by disrupting FTase-microtubule association.
• FTalphaKD cells exhibited increased sensitivity to Taxol and lonafarnib.

Conclusions:

• FTase is a critical upstream regulator of HDAC6 activity through its association with microtubules.
• FTase-microtubule interaction is essential for maintaining HDAC6 activity.
• FTase expression may serve as a biomarker for stratifying cancer patients who would benefit from FTI or Taxol treatment.