A metabolic switch controls intestinal differentiation downstream of <i>Adenomatous</i> polyposis coli (APC).

Abstract

Elucidating signaling pathways that regulate cellular metabolism is essential for a better understanding of normal development and tumorigenesis. Recent studies have shown that <i>mitochondrial pyruvate carrier 1 (MPC1)</i>, a crucial player in pyruvate metabolism, is downregulated in colon adenocarcinomas. Utilizing zebrafish to examine the genetic relationship between <i>MPC1</i> and <i>Adenomatous polyposis coli (APC),</i> a key tumor suppressor in colorectal cancer, we found that <i>apc</i> controls the levels of <i>mpc1</i> and that knock down of <i>mpc1</i> recapitulates phenotypes of impaired <i>apc</i> function including failed intestinal differentiation. Exogenous human <i>MPC1 RNA</i> rescued failed intestinal differentiation in zebrafish models of <i>apc</i> deficiency. Our data demonstrate a novel role for <i>apc</i> in pyruvate metabolism and that pyruvate metabolism dictates intestinal cell fate and differentiation decisions downstream of <i>apc</i>.