SOX4/HDAC2 Axis Enhances Cell Survivability and Reduces Apoptosis by Activating AKT/MAPK Signaling in Colorectal Cancer

Background: Increased SOX4 (SRY-related HMG-box) activity aids cellular transformation and metastasis. However, its specific functions and downstream targets remain to be completely elusive in colorectal cancer (CRC).

Aims: To investigate the role of SOX4 in CRC progression and the underlying mechanism.

Methods: In the current study, online available datasets of CRC patients were explored to check the expression status of SOX4. To investigate the further functions, SOX4 was overexpressed and knocked down in CRC cells. Colony formation assay, flowcytometry analysis, and MTT assay were used to check for proliferation and apoptosis. Acridine orange staining was done to check the role of SOX4 in autophagy induction. Furthermore, western blot, qRT-PCR, and bioinformatic analysis was done to elucidate the downstream molecular mechanism of SOX4.

Results: GEPIA database showed enhanced expression of SOX4 mRNA in CRC tumor, and the human protein atlas (HPA) showed strong staining of SOX4 protein in tumor when compared to the normal tissue. Ectopic expression of SOX4 enhanced colony formation ability as well as rescued cells from apoptosis. SOX4 overexpressed cells showed the formation of acidic vesicular organelles (AVOs) which indicated autophagy. Further results revealed the activation of p-AKT/MAPK molecules upon overexpression of SOX4. SOX4 expression was found to be positively correlated with histone deacetylase 2 (HDAC2). Knockdown of SOX4 or HDAC2 inhibition induced apoptosis, revealed by decrease in BCL2 and increase in BAX expression, and inactivated the p-AKT/MAPK signaling.

Conclusion: The study uncovers that SOX4/HDAC2 axis improves cell survivability and reduces apoptosis via activation of the p-AKT/MAPK pathway.