Alterations in cholesterol sulfate and its biosynthetic enzyme during multistage carcinogenesis in mouse skin

Recent evidence suggests that cholesterol sulfate may be an important secon d messenger involved in signaling epidermal differentiation in skin. The ac tivity of cholesterol sulfotransferase (Ch-ST) is increased during squamous differentiation of keratinocytes and is believed to be a marker enzyme for terminal differentiation. The primary objective of this study was to exami ne changes in levels of cholesterol sulfate (CS) and activity of its biosyn thetic enzyme, Ch-ST, during multistage carcinogenesis in mouse skin. Using SENCAR mice, we determined the activity of Ch-ST in normal epidermis, in t umor promoter-treated epidermis, in epidermis during wound healing, and in mouse skin tumors generated by initiation-promotion regimens. A single topi cal application of tumor promoters led to significantly elevated levels of Ch-ST activity and of CS. Epidermal Ch-ST activity was also elevated during wound healing. Dramatic increases in CS levels and in the activity of Ch-S T were found in nearly all of the papillomas and squamous cell carcinomas e xamined. The increased levels of CS and activity of Ch-ST in tumor promoter -treated epidermis were accompanied by increased transglutamin-ase-I activi ty. In contrast, transglutaminase I activity was not elevated in primary pa pillomas or squamous cell carcinomas, Finally, Ch-ST activity was significa ntly elevated in the epidermis of newborn HK1.ras transgenic mice, whereas transglutaminase I activity did not correlate with Ch-ST activity in these mice. These results demonstrate that diverse tumor-promoting stimuli all pr oduce elevated CS levels and Ch-ST activity and that CS levels and Ch-ST ac tivity were constitutively elevated in both papillomas and squamous cell ca rcinomas. The data also suggest a mechanism for upregulation of Ch-ST in sk in tumors involving activation/upregulation of Ha-ras.