Doctoral Dissertations

Date of Award

5-2017

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Nutritional Sciences

Major Professor

Dallas R. Donohoe

Committee Members

Jay Whelan, Zhao Ling, Todd Reynolds

Abstract

The prohibitory effects of dietary fiber in colorectal cancer have been identified, although the detailed mechanism of this beneficial effect remain unclear. Butyrate, a fermentation metabolite of fiber, has anti-cancer properties by inhibiting cell proliferation and increasing cell apoptosis in cancer cells. A major mechanism, whereby butyrate exerts anti-cancer effects in colorectal cancer, is its role as an HDAC inhibitor. Moreover, it has been suggested that the metabolic fate of butyrate is significantly related to its role as an HDAC inhibitor. Therefore, understanding butyrate metabolism in cancerous colonocytes sheds important light on how butyrate has its selective and inhibitory effects toward colorectal cancer.

This dissertation reports (1) colorectal cancer cells exhibit reduced ability to oxidize butyrate; (2) the mechanisms of butyrate oxidation are carnitinedependent and carnitine-independent in colorectal cancer cells; (3) the Warburg effect, inactivation of pyruvate dehydrogenase (PDH), is a critical event to repress the carnitine-dependent butyrate oxidation in colorectal cancer cells. Also, this dissertation further describes that (1) butyrate suppresses its own oxidation by regulating short-chain acyl dehydrogenase (SCAD) levels in colorectal cancer cells; (2) butyrate acts as an HDAC inhibitor and (3) selectively inhibits HDAC 1 in order to suppress SCAD expression in colorectal cancer cells.

These findings bridge the important relationship between butyrate metabolism and its epigenetic role in order to explain its inhibitory effects in colorectal cancer cells. Also, the results raise a key question (Why is butyrate regulation in its own oxidation in colorectal cancer cells?) for future studies that may discover other mechanisms of the preventive effects of butyrate in colorectal cancer.

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