Histone Methyltransferases as a New Target for Epigenetic Action of Vorinostat

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Varvara Maksimova^1#, Julia Makus^1,2#, Valeriia Popova^1,3, Anzhelika Prus^1,4, Olga Usalka^1,5, Ekaterina Trapeznikova⁵, Ekaterina Zhidkova¹, Gennady Belitsky¹, Marianna Yakubovskaya¹, and Kirill Kirsanov^1,2,a*

¹Blokhin National Medical Research Center of Oncology, 115478 Moscow, Russia

²Peoples’ Friendship University of Russia, 117198 Moscow, Russia

³Dmitry Mendeleev University of Chemical Technology of Russia, 125047 Moscow, Russia

⁴MIREA, Russian Technological University, 119571 Moscow, Russia

⁵Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), 119991 Moscow, Russia

^# These authors contributed equally to this study.

^* To whom correspondence should be addressed.

Received February 2, 2023; Revised April 13, 2023; Accepted April 20, 2023

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Epigenetic genome regulation during malignant cell transformation is characterized by the aberrant methylation and acetylation of histones. Vorinostat (SAHA) is an epigenetic modulator actively used in clinical oncology. The antitumor activity of vorinostat is commonly believed to be associated with the inhibition of histone deacetylases, while the impact of this drug on histone methylation has been poorly studied. Using HeLa TI cells as a test system allowing evaluation of the effect of epigenetically active compounds from the expression of the GFP reporter gene and gene knockdown by small interfering RNAs, we showed that vorinostat not only suppressed HDAC1, but also reduced the activity of EZH2, SUV39H1, SUV39H2, and SUV420H1. The ability of vorinostat to suppress expression of EZH2, SUV39H1/2, SUV420H1 was confirmed by Western blotting. Vorinostat also downregulated expression of SUV420H2 and DOT1L enzymes. The data obtained expand our understanding of the epigenetic effects of vorinostat and demonstrate the need for a large-scale analysis of its activity toward other enzymes involved in the epigenetic genome regulation. Elucidation of the mechanism underlying the epigenetic action of vorinostat will contribute to its more proper use in the treatment of tumors with an aberrant epigenetic profile.

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KEY WORDS: malignant neoplasms with aberrant epigenetic profile, vorinostat, SAHA, histone methylation, histone methyltransferase (HMT), HeLa TI test system, SUV39H1, SUV39H2, EZH2, SUV420H1, SUV420H2, DOT1L

DOI: 10.1134/S000629792307009X

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