Research Paper Volume 14, Issue 11 pp 4653—4672
Histone deacetylase 4 reverses cellular senescence via DDIT4 in dermal fibroblasts
- 1 Department of Dermatology, Seoul National University College of Medicine, Seoul, Republic of Korea
- 2 Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Republic of Korea
- 3 Institute of Human-Environment Interface Biology, Medical Research Center, Seoul National University, Seoul, Republic of Korea
- 4 Department of New Biology, DGIST, Daegu, Republic of Korea
- 5 Department of Biological Sciences, Seoul National University, Seoul, Republic of Korea
- 6 Institute on Aging, Seoul National University, Seoul, Republic of Korea
Received: December 9, 2021 Accepted: May 7, 2022 Published: June 9, 2022https://doi.org/10.18632/aging.204118
How to Cite
Copyright: © 2022 Lee et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Histone deacetylases (HDACs) remove acetyl groups from lysine chains on histones and other proteins and play a crucial role in epigenetic regulation and aging. Previously, we demonstrated that HDAC4 is consistently downregulated in aged and ultraviolet (UV)-irradiated human skin in vivo. Cellular senescence is a permanent cell cycle arrest induced by various stressors. 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). RNA sequencing after overexpression or knockdown of HDAC4 in primary HDFs 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. Indeed, DDIT4 and HDAC4 expressions were downregulated during oxidative stress- and UV-induced senescence. HDAC4 overexpression rescued the senescence-induced decrease in DDIT4 and senescence phenotype, which were prevented by DDIT4 knockdown. In addition, 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.