P4HA1 regulates human colorectal cancer cells through HIF1α-mediated Wnt signaling

Colorectal cancer (CRC) is the third most commonly diagnosed malignancy that is associated with high levels of mortality. CRCs are often associated with an aberrant wingless-type mouse mammary tumor virus integration site family (Wnt) signaling pathway known to be responsible for tumorigenesis and cancer progression. Other factors that contribute to CRC pathology include hypoxia, extracellular matrix and cellular microenvironment. In the present study, modulation of Wnt, a common molecular progenitor for CRC-associated pathology was evaluated. CRC tissues and specific cell lines were found to exhibit increased expression levels of prolyl 4-hydroxylase subunit alpha 1 (P4HA1). P4HA1 expression was found to stabilize hypoxia inducible factor-1 alpha (HIF1 alpha). The silencing of P4HA1 resulted in decreased cell proliferation, cell cycle arrest in the G(1) phase, decreased tumorsphere formation, decreased tumorsphere volume, increased susceptibility to 5-fluorouracil and increased caspase-3 activity. However, P4HA1 silencing resulted in the activation and thus proteasomal degradation of beta-catenin, indicative of the abrogation of Wnt signaling pathway. Wnt is a critical signaling pathway and is activated in most CRCs. HIF1 alpha is a poor prognostic marker in CRC. The present study provided preliminary evidence that HIF1 alpha and the Wnt signaling pathway in CRC are modulated through P4HA1. P4HA1 may serve not just as a biomarker for CRC prognosis but may also be targeted for potential therapeutic intervention.

Automated summary

Colorectal cancer (CRC) is commonly associated with high mortality rates and an aberrant Wnt signaling pathway. This study found that increased expression of prolyl 4-hydroxylase subunit alpha 1 (P4HA1) in CRC tissues and cell lines stabilized hypoxia inducible factor-1 alpha (HIF1 alpha), leading to cell proliferation and tumorigenesis. Silencing P4HA1 decreased cell proliferation, cell cycle arrest, tumorsphere formation, and increased susceptibility to chemotherapy, showing the potential of P4HA1 as a biomarker and therapeutic target for CRC.