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HDAC5 loss impairs RB repression of oncogenic related genes and confers CDK4/6 inhibitor resistance in cancer [RNA-seq]

ABSTRACT: The tumor suppressor protein RB acts as a transcription repressor via the interaction of its pocket domain with an L/IXCXE motif in HDAC proteins such as HDAC1. Here we demonstrated that while lacking an L/IXCXE motif, HDAC5 interacts with both RB-N (via an FXXXV motif) and RB-C segments and this interaction is diminished by RB serine-249/threonine-252 and threonine-821 phosphorylation. HDAC5 gene is frequently downregulated or deleted in human cancers such as prostate cancer. Loss of HDAC5 increases histone H3 lysine 27 acetylation (H3K27-ac) and circumvents RB-mediated repression of cell cycle-related oncogenic genes. Accordingly, HDAC5 loss confers resistance to the CDK4/6 inhibitors such as Palbociclib in prostate cancer cells in vitro and in mice, but this effect is overcome by the BET-CBP/p300 dual inhibitor NEO2734. Our findings reveal an unknown role of HDAC5 in RB-mediated histone deacetylation and gene repression and a mechanism modulating CDK4/6 inhibitor therapeutic sensitivity in cancer cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE155001 | GEO | 2021/07/24

REPOSITORIES: GEO

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HDAC5 loss impairs RB repression of oncogenic related genes and confers CDK4/6 inhibitor resistance in cancer [ChIP-seq]

Project description:The tumor suppressor protein RB acts as a transcription repressor via the interaction of its pocket domain with an L/IXCXE motif in HDAC proteins such as HDAC1. Here we demonstrated that while lacking an L/IXCXE motif, HDAC5 interacts with both RB-N (via an FXXXV motif) and RB-C segments and this interaction is diminished by RB serine-249/threonine-252 and threonine-821 phosphorylation. HDAC5 gene is frequently downregulated or deleted in human cancers such as prostate cancer. Loss of HDAC5 increases histone H3 lysine 27 acetylation (H3K27-ac) and circumvents RB-mediated repression of cell cycle-related oncogenic genes. Accordingly, HDAC5 loss confers resistance to the CDK4/6 inhibitors such as Palbociclib in prostate cancer cells in vitro and in mice, but this effect is overcome by the BET-CBP/p300 dual inhibitor NEO2734. Our findings reveal an unknown role of HDAC5 in RB-mediated histone deacetylation and gene repression and a mechanism modulating CDK4/6 inhibitor therapeutic sensitivity in cancer cells.

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