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Increased Steroid Responsiveness during Sodium Butyrate-induced "Differentiation" of HeLa S₃ Cells^*

BRUCE A. LITTLEFIELD and JOHN A. CIDLOWSKI

Department of Biochemistry, University of Vermont College of Medicine Burlington, Vermont 05405
Departments of Physiology, Biochemistry and Nutrition, University of North Carolina at Chapel Hill Chapel Hill, North Carolina 27514

Address requests for reprints to: Dr. John A. Cidlowski, Department of Physiology, Biochemistry, and Nutrition, Room 460, Medical Research Building, University of North Carolina, Chapel Hill, North Carolina 27514.

Abstract

Pretreatment of HeLa S₃ cells with 5 mM sodium n-butyrate markedly enhances cellular responsiveness to the synthetic glucocorticoid dexamethasone, using increased alkaline phosphatase activity as a marker for steroid action. In contrast, dexamethasone pretreatment does not affect the responses of cells to butyrate. Maximal effects of butyrate on steroid responsiveness occur after 2 days of pretreatment. The increased responsiveness of butyrate-pretreated cells to dexamethasone is partially explained by the collection of most cells at a block point in the hormonally responsive portion of the Gl phase of the cell cycle. Cell cycle population effects on steroid responsiveness are lost only gradually over 40 h after the release from butyrate, as cells leave the hormonally responsive late Gl and S phases. In addition to cell cycle population effects, a second, more rapidly reversible effect of butyrate on steroid responsiveness occurs within the late Gl phase itself at the butyrate block point. This second effect is fully and rapidly lost within 10 h after butyrate’s removal, a time before the entry of the released cells into S phase. The reversal of butyrate-induced histone hyperacetylation was examined during this 10-h period. Hyperacetylation is lost in less than 2.5 h after butyrate’s removal, suggesting that a rapidly reversible enhancement of glucocorticoid action may occur in the late Gl phase when histones are hyperacetylated. This rapidly reversible process appears to be distinct from the more slowly reversible cell cycle population effects. (Endocrinology 114: 566, 1984)

Footnotes

^* This work was supported by NIH Grant AM-20892 and Training Grant T32-CA-09286.

Present address: Department of Cell Biology, Section of Biochemistry, Mayo Clinic, Rochester, Minnesota 55905.

Received March 17, 1983.

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