Inhibition of HDAC6 alters fumarate hydratase activity and mitochondrial structure

Authors:

Andrew Roe, Catríona M. Dowling, Cian D’Arcy, Daniel Alencar Rodrigues, Yu Wang, Matthew Hiller, Carl Keogh, Kate E. R. Hollinshead, Massimiliano Garre, Brenton Cavanagh, Kieran Wynne, Tianyan Liu, Zhixing Chen, Emma Kerr, Marie McIlroy, Jochen H. M. Prehn, Ingmar Schoen, Tríona Ní Chonghaile

Keywords:

Cancer metabolism; Super-resolution microscopy; Targeted therapies; Fumarate hydratase; mitochondria; tumor suppressor; HDAC6; cristae

Abstract:

Fumarate hydratase (FH), a key node of mitochondrial metabolism, is also a tumour suppressor. Despite its prominent roles in tumourigenesis and inflammation, its regulation remains poorly understood. Herein, we show that histone deacetylase 6 (HDAC6) regulates FH activity. In triple-negative breast cancer cells, HDAC6 inhibition or knockdown results in alterations to mitochondrial cristae structure, as detected by live-cell super-resolution STED nanoscopy and electron microscopy, along with the release of mitochondrial DNA. Mass-spectrometry immunoprecipitation reveals multiple mitochondrial HDAC6-interactors, with FH emerging as a top hit. Super-resolution 3D-STORM shows HDAC6 interactions with FH in mitochondrial networks, which increases after perturbation of HDAC6 activity with BAS-2. Treatment with BAS-2 leads to fumarate accumulation by ¹³C glucose labelling, along with downstream succination of proteins and cell death. Together, these results identify HDAC6 inhibition as a regulator of endogenous FH activity in tumour cells, and highlight it as a promising candidate for indirectly targeting tumour metabolism.

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