HDAC5 Loss Impairs RB Repression of Pro-Oncogenic Genes and Confers CDK4/6 Inhibitor Resistance in Cancer

Abstract

The tumor-suppressor protein RB acts as a transcription repressor via interaction of its pocket domain with an LXCXE motif in histone deacetylase (HDAC) proteins such as HDAC1. Here, we demonstrate that HDAC5 deficient for the LXCXE motif interacts with both RB-N (via an FXXXV motif) and RB-C segments, and such interactions are diminished by phosphorylation of RB serine-249/threonine-252 and threonine-821. HDAC5 was frequently downregulated or deleted in human cancers such as prostate cancer. Loss of HDAC5 increased histone H3 lysine 27 acetylation (H3K27-ac) and circumvented RB-mediated repression of cell-cycle–related pro-oncogenic genes. HDAC5 loss also conferred resistance to CDK4/6 inhibitors such as palbociclib in prostate and breast cancer cells in vitro and prostate tumors in vivo, but this effect was 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 define a new mechanism modulating CDK4/6 inhibitor therapeutic sensitivity in cancer cells. Significance: This study defines a previously uncharacterized role of HDAC5 in tumor suppression and provides a viable strategy to overcome CDK4/6 inhibitor resistance in HDAC5-deficent cancer.

Promoter Demethylation Upregulates STEAP1 Gene Expression in Human Prostate Cancer: In Vitro and In Silico Analysis

“…In fact, the HDAC family modulates several genes involved in cancer development/progression via angiogenesis, cell adhesion, migration and invasion [22]. Some studies support our results, showing that increased expression of autotaxin in PCa cell lines is mediated by the downregulation of HDAC7 and HDAC3 [37]; additionally, HDAC5 is downregulated in human cancer, namely PCa [38], and decreased expression of HDAC4 increases the growth of PCa cells [39]. On the other hand, there are also studies showing an overexpression of HDAC in several types of cancer, suggesting the use of HDAC inhibitors as a promising class of compounds for cancer treatment [40][41][42][43].…”

Insights Into the Function and Clinical Application of HDAC5 in Cancer Management

“…Electron microscopy and immunohistochemical analyses of HDAC5 subcellular localization revealed that HDAC5 was associated with heterochromatin in S and G1 phases, suggesting a role in DNA replication and cell cycle progression ( 79 ). For example, HDAC5 silencing shielded cell-cycle of prostate cancer cells from RB-mediated repression ( 80 ). Knockdown of HDAC5 also induced G1 cell cycle arrest, which hindered breast cancer proliferation ( 50 ).…”

HDAC5 modulates PD-L1 expression and cancer immunity via p65 deacetylation in pancreatic cancer

“…Class IIa members were thought to be distinct to other HDACs in terms of molecular weight and the limited enzymatic activity 14 . Furthermore, our previous research found that HDAC5 work with retinoblastoma protein (RB) through a completely different binding motif compared to that of Class I HDACs 48 . This phenomenon also helps us to explain the diversity of different HDACs.…”

“…More interestingly, HDAC5 itself also plays different roles in different tumors 15 , 16 . And its function will also change due to the different subtypes in the same tumor, ER status determines the effect of HDAC5 on the vulnerability to CDK4/6 inhibitors in breast cancer 48 . This complexity also indicated that more investigation is needed to clarify the underlying regulatory mechanism.…”