Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.780397
Title: Exploring TLR adaptor protein MyD88 as a sensitivity determinant to HDAC inhibitors
Author: Bekheet, Mina
ISNI:       0000 0004 7966 0414
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2017
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Abstract:
Carcinogenesis has shown to be a result of aberrant genetic as well as epigenetic processes. Histone Deacetylase (HDAC) inhibitors, a class of therapeutic agents developed against the latter, have been shown to be efficient against certain haematological malignancies. However, the underlying molecular mechanisms are still largely unknown. An unbiased loss-of-function screen was used to identify genes that govern cellular sensitivity to HDAC inhibitors (HDIs). Myeloid differentiation primary response 88 (MyD88), a Toll-like receptor (TLR) adaptor protein, was identified as a key regulator of the anti-proliferative effects of HDIs, whereas levels of MyD88 were found to govern cells response to HDI treatment through regulating cytokines levels. Furthermore, MyD88 L265P, its most abundant loss-of-function mutation, was associated with increased cell sensitivity to HDIs. It was also found that MyD88 acetylation status contributed to its regulation via an HDAC6-dependant interaction. These results suggested that through scrutinising the underlaying molecular pathways that become altered during tumourigenesis there could be important relative prognostic and diagnostic values for cancer treatment in clinical settings; whereas levels of MyD88, its acetylation status, or the expression of its L265P mutant; could represent a valuable set of indicators to identify subsets of patients who are more likely to respond positively to HDI treatment.
Supervisor: Thangue, Nicholas La Sponsor: Yousef Jameel Academic Program
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.780397  DOI: Not available
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