Unscheduled HDAC4 repressive activity in human fibroblasts triggers TP53‐dependent senescence and favors cell transformation

Abstract

Expression of the class IIa HDACs is frequently altered in different human cancers. In mouse models these transcriptional repressors can trigger transformation, acting as bona fide oncogenes. Whether class IIa HDACs also exhibit transforming activities in human cells is currently unknown. We infected primary human fibroblasts with retroviruses to investigate the transforming activity of HDAC4 in cooperation with well‐known oncogenes. We have discovered that HDAC4 triple mutant (S246A, S467A, S632A) (HDAC4‐TM), a nuclear resident version of the deacetylase, triggers TP53 stabilization and OIS (oncogene‐induced senescence). Unlike RAS, HDAC4‐induced OIS was TP53‐dependent and characterized by rapid cell cycle arrest and accumulation of an unusual pattern of γH2AX‐positive foci. The inactivation of both TP53 and of the retinoblastoma (pRb) tumor suppressors, as induced by the viral oncogenes large and small T of SV40, triggers anchorage‐independent growth in RAS, HDAC4‐TM and, to a lesser extent, in HDAC4‐wild type (WT)‐expressing cells. Our results suggest an oncogenic function of class IIa HDACs in human cells, and justify further efforts to discover and evaluate isoform‐specific inhibitors of these epigenetic regulators from a therapeutic perspective.

HDAC7‐mediated control of tumour microenvironment maintains proliferative and stemness competence of human mammary epithelial cells

“…The contribution of class IIa HDACs to cell proliferation and transformation is underestimated. There are some evidences about the transforming potential of HDAC7 and its activity as oncogene (Di Giorgio et al ., ; Lei et al ., ; Paluvai et al ., ; Peixoto et al ., ; Rad et al ., ). Here, we have proved that, in human mammary epithelial cells, HDAC7 influences multiple aspects of the transformation process including proliferation, invasion and stemness.…”

The Histone Code of Senescence

“…The expression of a certain number of oncogenes (K-RAS and H-RAS, BRAFV600E, myrAKT1, STAT5, nuclear HDAC4, N1ICD, ERBB2 and β-catenin) [84][85][86][87][88][89][90][91][92] or ablation of tumor suppressors (PTEN, APC and AXIN) in normal cells triggers a permanent and premature cell-cycle arrest defined as OIS [93,94]. OIS can occur also in the presence of ectopic TERT expression [6].…”

Genetic Programs Driving Oncogenic Transformation: Lessons from In Vitro Models

“…Here, we deeply investigated the strength of the transcriptome reprogramming, triggered during the in vitro transformation process, in predicting the outcome of different human cancers. With this aim we compared the gene expression profiles of human foreskin fibroblasts expressing hTERT, the early region of SV40 and subsequently transduced with HRAS/G12V [13], MYC [14], or an oncogenic nuclear resident form of HDAC4 (HDAC4-TM) [13,15]. These oncogenes have been chosen for their heterogeneity.…”

“…To prove the above enounced concept, we interrogated the gene expression profiles of BJ-hTERT/ST/LT/MYC [14], BJ-hTERT/ST/LT/HRASG12V [13], and BJ-hTERT/ST/LT/HDAC4-S246A, S467A, S632A [15], relatively to the isogenic pre-transformed control cells, expressing the SV40 LT and ST or the entire early region.…”

“…The transcriptional profiles of the three isogenic transformation models were obtained by re-analyzing the datasets GSE17941 [13], GSE72530 [14], and GSE120040 [15] deposited as raw files in GEO (Gene Expression Omnibus). The CEL files were processed with affy package in R [76].…”