HDAC11 regulates Alternative Splicing of Androgen Receptor Variant 7 via De-fatty Acylation of Splicing Factor 3B Subunit 2
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Histone Deacetylase 11 (HDAC11) is a member of the HDAC protein family, which are enzymes that regulate epigenetic gene expression. However, many HDACs deacetylate non-histone proteins and can also remove post translational modifications other than acetylation. Furthermore, HDACs have been implicated in diverse molecular processes beyond just epigenetics. This includes signal transduction, protein stabilization and degradation, RNA splicing, and other processes. In the case of RNA splicing, however, there has been no direct evidence provided as to how HDACs are involved. This work aimed to close this gap in the field by establishing how HDAC11 is involved in RNA splicing regulation. It is known that HDAC11 possesses a unique catalytic function of lysine de-fatty acylation and HDAC11 is capable of regulating non-histone proteins via de-fatty acylation. This dissertation work establishes that HDAC11 directly regulates the RNA slicing factor SF3B2 through de-fatty acylation, marking the first time that any HDAC has been shown to regulate an RNA binding protein. De-fatty acylation of SF3B2 by HDAC11 is dependent on HDAC11 catalytic activity, and the SF3B2 residue under regulation is Lysine (K) 10. SF3B2 K10 can also be SUMOylated, and HDAC11 can modulate the SUMOylation of K10 by removal of the competing K10 fatty acylation. Because SUMOylation is required for efficient RNA splicing, this is one mechanism by which HDAC11 could influence splicing. In liver cancer cells, the de-fatty acylated SF3B2 mimic, which is the K10R mutation, displayed enhanced RNA binding capability, causing increased alternative RNA splicing of Androgen Receptor variant 7 (AR-v7). AR-v7 is oncogenic in liver cancer and is heavily studied in prostate cancer. In prostate cancer cells, however, de- fatty acylated SF3B2 and HDAC11 had no effect on AR-v7 expression or splicing. This work represents the first instance of any HDAC directly regulating RNA biology and is of significant impact to the field of HDACs and HDACs in cancer. In liver cancer, both high HDAC11 and SF3B2 expression are prognostic towards patient death. This dissertation establishes how HDAC11 and SF3B2 work together in liver cancer cells to regulate the AR-v7 oncogene.
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