Preferential Upregulation of AMOT-p80 Is Associated with YAP-Linked Resistance to 5-Fluorouracil and Oxaliplatin in Colorectal Cancer Cells

Resistance to 5-fluorouracil (5-FU) and oxaliplatin (OXA) remains an obstacle in colorectal cancer (CRC) therapy, but the upstream mechanisms enabling adaptive survival remain unclear. Angiomotin (AMOT), a Hippo-YAP regulator, is expressed as two major isoforms, p130 and p80, but the contribution of isoform-specific AMOT regulation to chemoresistance is unknown. RNA-seq of OXA-resistant cells identified AMOT as a candidate determinant, and its isoform-specific regulation and functional relevance were then examined in OXA- and 5-FU-resistant CRC sublines. AMOT-p80 was preferentially upregulated, whereas AMOT-p130 remained largely unchanged. Common AMOT pre-mRNA was elevated, whereas p130-specific pre-mRNA was unchanged, consistent with preferential transcriptional activation favoring the p80 isoform. Functionally, AMOT depletion minimally affected basal viability but significantly sensitized resistant cells to 5-FU or OXA, with increased apoptotic responses. AMOT silencing reduced nuclear YAP and lowered c-Myc and Cyclin D1 protein levels, whereas AMOT-p80 re-expression restored nuclear YAP, with recovery of c-Myc/Cyclin D1 levels and drug tolerance. YAP knockdown attenuated these outputs and blunted the additional effect of AMOT depletion. AMOT-p80 overexpression in parental cells increased c-Myc/Cyclin D1 protein levels and enhanced tolerance to 5-FU and OXA. These findings suggest that preferential AMOT-p80 upregulation is linked to YAP-associated chemoresistant phenotypes in CRC cells.