Aging-US | DDIT4 Identified as Candidate Target of HDAC4-Associated Skin Aging


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BUFFALO, NY- June 15, 2022 – A new research paper was published in Aging (Aging-US) on the cover of Volume 14, Issue 11, entitled, “Histone deacetylase 4 reverses cellular senescence via DDIT4 in dermal fibroblasts.”

Researchers—from Seoul National University, Seoul National University College of Medicine, Seoul National University Graduate School, and Daegu Gyeongbuk Institute of Science and Technology (DGIST)—previously demonstrated that histone deacetylase 4 (HDAC4) is consistently downregulated in aged and ultraviolet (UV)-irradiated human skin. However, there is little research on how HDAC4 causes skin aging.

“To elucidate the potential role of HDAC4 in the regulation of cellular senescence and skin aging, we established oxidative stress- and UV-induced cellular senescence models using primary human dermal fibroblasts (HDFs).”

After overexpression or knockdown of HDAC4 in primary HDFs, RNA sequencing identified candidate molecular targets of HDAC4. 

“Integrative analyses of our current and public mRNA expression profiles identified DNA damage-inducible transcript 4 (DDIT4) as a critical senescence-associated factor regulated by HDAC4.”

Although DDIT4 function has been investigated extensively in the fields of cancer and autophagy, little is known about its role in skin aging. The researchers found that DDIT4 expression was markedly reduced in aged skin in vivo, in replicative senescent HDFs, and in senescent fibroblasts under repeated H₂O₂ treatment or UV irradiation. During oxidative stress- and UV-induced senescence, both DDIT4 and HDAC4 expressions were downregulated. 

Figure 2. Integrative transcriptome analysis identifies DDIT4 as a candidate target.

In addition, the overexpression of HDAC4 rescued cells from the senescence-induced decrease in DDIT4 and senescence phenotype (which were prevented by DDIT4 knockdown). DDIT4 overexpression reversed changes in senescence-associated secretory phenotypes and aging-related genes, suggesting that DDIT4 mediates the reversal of cellular senescence via HDAC4. 

“Collectively, our results identify DDIT4 as a promising target regulated by HDAC4 associated with cellular senescence and epigenetic skin aging.”

“These results provide novel insights into the regulatory role of the HDAC4-DDIT4 pathway in epigenetic skin aging.”


Corresponding Authors: Daehee Hwang -, Dong Hun Lee -, Jin Ho Chung - 

Keywords: cellular senescence, DNA damage-inducible transcript 4, histone deacetylase 4, oxidative stress, ultraviolet light

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