- Title
- Cooperativity of HOXA5 and STAT3 is critical for HDAC8 inhibition-mediated transcriptional Activation of PD-L1 in human melanoma cells
- Creator
- Wang, Yu Fang; Liu, Fen; Sherwin, Simonne; Farrelly, Margaret; Yan, Xu Guang; Croft, Amanda; Liu, Tao; Jin, Lei; Zhang, Xu Dong; Jiang, Chen Chen
- Relation
- Funding BodyNHMRCGrant Number1083496 http://purl.org/au-research/grants/nhmrc/1083496
- Relation
- Journal of Investigative Dermatology Vol. 138, Issue 4, p. 922-932
- Publisher Link
- http://dx.doi.org/10.1016/j.jid.2017.11.009
- Publisher
- Nature Publishing Group
- Resource Type
- journal article
- Date
- 2018
- Description
- Although the expression of programmed death-ligand 1 (PD-L1) is an important mechanism by which cancer cells evade the immune system, PD-L1 expression in cancer cells is commonly associated with patients' responses to treatment with anti-programmed death 1/PD-L1 antibodies. However, how PD-L1 expression is regulated in melanoma cells remains to be fully elucidated. Here we report that the class I histone deacetylase (HDAC) HDAC8 controls transcriptional activation of PD-L1 by a transcription complex consisting of transcription factors homeobox A5 and signal transducer and activator of transcription 3. Inhibition of HDAC8 upregulated PD-L1 in melanoma cells. This was due to an increase in the activity of a fragment of the PD-L1 gene promoter that is enriched with binding sites for both homeobox A5 and signal transducer and activator of transcription 3. Indeed, knockdown of homeobox A5 or signal transducer and activator of transcription 3 abolished upregulation of PD-L1 by HDAC8 inhibition. Moreover, homeobox A5 and signal transducer and activator of transcription 3 were physically associated and appeared interdependent in activating PD-L1 transcription. Functional studies showed that HDAC8-mediated regulation of PD-L1 expression participated in modulating anti-melanoma T-cell responses. Collectively, these results identify HDAC8 as an important epigenetic regulator of PD-L1 expression, with implications for better understanding of the interaction between melanoma cells and the immune system.
- Subject
- melanoma cells; cancer cells; immune system; programmed death-ligand 1 (PD-L1); cancer treatment
- Identifier
- http://hdl.handle.net/1959.13/1390039
- Identifier
- uon:32982
- Identifier
- ISSN:0022-202X
- Rights
- © 2018. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/.
- Language
- eng
- Full Text
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