Involvement of histone deacetylase 1/2 in adrenocorticotropic hormone synthesis and proliferation of corticotroph tumor AtT-20 cells

Peptides. 2021 Feb:136:170441. doi: 10.1016/j.peptides.2020.170441. Epub 2020 Nov 9.

Abstract

Cushing's disease is mainly caused by autonomous production of adrenocorticotropic hormone (ACTH) from pituitary adenomas. In our previous study, a histone deacetylase (HDAC) inhibitor, trichostatin A, inhibited cell proliferation and ACTH production via decreased pituitary tumor-transforming gene 1 (PTTG1) in AtT-20 mouse corticotroph tumor cells. In the present study, we examined the effects of romidepsin, a potent and selective HDAC1/2 inhibitor, on cell proliferation and ACTH synthesis. To elucidate further potential mechanisms of romidepsin, we examined the effects of HDAC1/2 on proopiomelanocortin (Pomc) and Pttg1 mRNA levels and cell proliferation. Small interfering RNA-mediated knockdown was used to decrease HDAC1 or 2. Romidepsin treatment decreased Pomc and Pttg1 mRNA levels, and cell proliferation. The drug also increased Hdac1 and decreased Hdac2 mRNA levels. Hdac1 knockdown decreased basal Pttg1 mRNA levels and cell proliferation, but not Pomc mRNA levels. Romidepsin treatment decreases ACTH synthesis in corticotroph tumor cells. Romidepsin suppresses cell proliferation via PTTG1. HDAC1 is also involved in the proliferation of corticotroph cells via PTTG1.

Keywords: Adrenocorticotropic hormone; Corticotroph tumor; Cushing’s disease; Histone deacetylase; Proopiomelanocortin.

MeSH terms

  • Adrenocorticotropic Hormone / biosynthesis
  • Adrenocorticotropic Hormone / genetics*
  • Animals
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Depsipeptides / pharmacology*
  • Disease Models, Animal
  • Histone Deacetylase 1 / antagonists & inhibitors
  • Histone Deacetylase 1 / genetics*
  • Histone Deacetylase 2 / antagonists & inhibitors
  • Histone Deacetylase 2 / genetics*
  • Humans
  • Hydroxamic Acids / pharmacology
  • Mice
  • Pituitary ACTH Hypersecretion / drug therapy*
  • Pituitary ACTH Hypersecretion / genetics
  • Pituitary ACTH Hypersecretion / pathology
  • Pituitary Neoplasms / drug therapy
  • Pituitary Neoplasms / genetics
  • Pituitary Neoplasms / pathology
  • Pro-Opiomelanocortin / genetics
  • RNA, Messenger / genetics
  • RNA, Small Interfering / genetics
  • Securin / antagonists & inhibitors
  • Securin / genetics*

Substances

  • Depsipeptides
  • Hydroxamic Acids
  • PTTG1 protein, mouse
  • RNA, Messenger
  • RNA, Small Interfering
  • Securin
  • trichostatin A
  • Pro-Opiomelanocortin
  • Adrenocorticotropic Hormone
  • romidepsin
  • Hdac1 protein, mouse
  • Hdac2 protein, mouse
  • Histone Deacetylase 1
  • Histone Deacetylase 2