Recently, the
fatty acid elongation enzyme ELOVL5 was identified as a critical pro-metastatic factor in
prostate cancer, required for cell growth and mitochondrial homeostasis. The
fatty acid elongation reaction catalyzed by ELOVL5 utilizes
malonyl-CoA as the
carbon donor. Here, we demonstrate that ELOVL5 knockdown causes
malonyl-CoA accumulation.
Malonyl-CoA is a cellular substrate that can inhibit
fatty acid β-oxidation in the mitochondria through allosteric inhibition of
carnitine palmitoyltransferase 1A (CPT1A), the
enzyme that controls the rate-limiting step of the long chain
fatty acid β-oxidation cycle. We hypothesized that changes in
malonyl-CoA abundance following ELOVL5 knockdown could influence mitochondrial β-oxidation rates in
prostate cancer cells, and regulate cell viability. Accordingly, we find that ELOVL5 knockdown is associated with decreased mitochondrial β-oxidation in
prostate cancer cells. Combining ELOVL5 knockdown with FASN inhibition to increase
malonyl-CoA abundance endogenously enhances the effect of ELOVL5 knockdown on
prostate cancer cell viability, while preventing
malonyl-CoA production rescues the cells from the effect of ELOVL5 knockdown. Our findings indicate an additional role for
fatty acid elongation, in the control of
malonyl-CoA homeostasis, alongside its established role in the production of long-chain
fatty acid species, to explain the importance of
fatty acid elongation for cell viability.