Notably HSP expression is under control of the
Notably, HSP27 expression is under control of the tetrameric form of CK2 holoenzyme, as knockout or knockdown of the β regulatory subunit alone reproduces the same effects of targeting the α/α′ catalytic subunits. This observation discloses the possibility to use more specific drugs that affects only the CK2 tetrameric formation without altering the total CK2 activity .
Finally, it should be highlighted that the pharmacological downregulation of HSP27 expression is of widespread interest, as other human diseases would also benefit from it. This especially applies to Cystic Fibrosis (CF)  considering that at least of phenylalanine at position 508 in Cystic fibrosis transmembrane conductance regulator (F508delCFTR), present in 70–90% of CF patients, maintains at least partially channel activity, but causes the majority of CFTR protein to be sequestered by chaperones. This leads to the recruitment of ubiquitin ligase ultimately resulting in CFTR ubiquitylation and its proteasomal degradation . Consequently F508delCFTR is >99% degraded before it can reach the plasma membrane . HSP27 is one of the chaperones that selectively bind and target F508delCFTR for degradation. Notably, the steady-state levels of F508del CFTR are affected by the modulation of HSP27 expression [40,, , ]. CK2 has been already proposed as a pharmacological target to treat F508del patients in the combinatorial therapy of cysteamine plus epigallocatechin-gallate, but its mechanism of implication in this intricate process is far from being fully understood . Further work will be necessary to verify if HSP27 downregulation could explain, at least partially, the effect of CK2 inhibitors in F508del patients.
The following are the supplementary data related to this article.
Acknowledgments This work was supported by Fondazione per la Ricerca sulla Fibrosi Cistica (grant FFC#10/2016 adopted by Gruppo di Sostegno FFC di Seregno and grant FFC#12/2017 adopted by Delegazione FFC di Fabriano Ancona con il Gruppo di Sostegno FFC di Umbertide Città di Castello Perugia) (to M.S.) and by the Associazione Italiana per la Ricerca sul Cancro (AIRC), grant number IG 18756 (to L.A.P.). J.V. was supported by a fellowship of the FFC (to M.S.). We are grateful to Prof. Oriano Marin (CRIBI, University of Padova, Italy) who provided the peptides for CK2 kinase activity assay, and Dr. Anna Cabrelle for her technical support with FACS sorting, HSP27-FLAG plasmid was kindly provided by Prof. Gary Brewer.
Introduction Cellular senescence is characterized by irreversible cell proliferation arrest that is triggered by several stimuli including telomere attrition, oxidative stress, and oncogenic activation. In vivo, senescence is thought to act as an important tumor suppression mechanism to eliminate dangerous cells and has also been suggested to cause tissue aging by exhausting renewable tissue stem cells [1,2]. Senescent cells have several molecular features and cytological markers: a large flat morphology, senescence-associated β-galactosidase activity (SA-β-gal), activation of the p53 and p21Cip1/WAF1 axis, senescence-associated secretory phenotype, and senescence-associated heterochromatin foci (SAHF) [, , ]. SAHF, which are visible as distinct DNA foci upon 4′,6-Diamidino-2-phenylindole (DAPI) staining of senescent cells, result from condensation of chromatin into characteristically punctate heterochromatic domains. SAHF formation represses the expression of genes encoding cell cycle progression-associated proteins such as cyclin A, proliferating cell nuclear antigen, and cyclin D1. SAHF contain various markers of transcriptionally silent heterochromatin, such as trimethylated histone H3 Lys 9 (H3K9me3) and heterochromatin proteins 1 (HP1α, β, and γ) [, , , , ]. The total amount of H3K9me3 is increased in the senescent cells and H3K9me3 is repositioned to the nuclear membrane nearby Lamin B . The methylation status of H3K9 can be regulated by specific histone methyltransferases (HMTs) including SUV39h1, G9a, GLP, and SETDB1, as well as histone demethylases including LSD1, JmjD1a, and JmjD2c [11,12]. These HMTs contain a conserved SET domain encoding methyl transferase activity, form a complex together, and cooperate in gene silencing . Among them, G9a and GLP (G9a-like protein) are principally responsible for mono- or di-methylation of H3K9 in euchromatin . SETDB1 alone dimethylates H3K9 but trimethylates this site when associated with mAM . In contrast, SUV39h1 mainly mediates tri-methylation of H3K9 using mono- or di-methylated H3K9 as a primary substrate . However, little is known about the mechanism underlying SAHF formation during cellular senescence.