SOX9 is an atypical intestinal tumor suppressor controlling the oncogenic Wnt/ß-catenin signaling

Area of Science:

• Molecular biology
• Oncology
• Genetics

Background:

• SOX9 inactivation is common in colorectal cancer (CRC), often due to mutations or MiniSOX9 expression.
• This inactivation contributes to the progression of colorectal cancer.

Purpose of the Study:

• To investigate the role of SOX9 in colorectal cancer.
• To determine if SOX9 exhibits tumor suppressor activity.

Main Methods:

• Identified a heterozygous inactivating SOX9 mutation (L142P) in DLD-1 CRC cells.
• Studied the effects of conditional wild-type SOX9 expression on CRC cell growth, Wnt/ß-catenin signaling, and c-myc expression.
• Assessed SOX9's impact on tumor development in mouse models (subcutaneous and intraperitoneal injections).
• Investigated the effect of SOX9 inhibition using siRNA.

Main Results:

• Conditional SOX9 expression inhibited DLD-1 CRC cell growth, clonal capacity, and colonosphere formation.
• SOX9 suppressed Wnt/ß-catenin signaling and c-myc expression, independent of its transcriptional function, via interaction with nuclear ß-catenin.
• SOX9 inhibited tumor development in mouse models.
• siRNA-mediated SOX9 knockdown paradoxically inhibited CRC cell growth, suggesting a critical level of SOX9 is needed for CRC cell maintenance.

Conclusions:

• SOX9 demonstrates tumor suppressor activity in colorectal cancer.
• A critical level of endogenous active SOX9 is necessary for maintaining colorectal cancer cell growth.