Enhanced Collagen Prolyl 4-Hydroxylase Activity and Expression Promote Cancer Progression via Both Canonical and Non-Canonical Mechanisms.

Collagens make up the main components of the extracellular matrix (ECM), and, in cancer, are often aberrantly secreted by both tumor cells and stromal cells in the tumor microenvironment (TME). Collagen prolyl 4-hydroxylase (C-P4H), an enzyme that hydroxylates proline into 4-hydroxyproline at the Y position of the collagen -X-Y-Gly- triplet motif, is essential for the stability of the mature collagen trimer and collagen secretion. In this review, we summarize the research on the structure and function of C-P4H, the regulation of C-P4H enzyme activity, and the role of overexpression of its α-subunit, P4HA1, in promoting cancer progression as well as its potential as a prognostic marker and therapeutic target. Overexpression of P4HA1 is displayed in almost all solid cancers, including breast, colorectal, and lung cancer, and is associated with cancer progression, worse response to therapy, and poorer patient survival. Characterization of P4HA1 overexpression has demonstrated links to key hallmarks of cancer, not only in the canonical collagen deposition role, but also in non-canonical functions, such as cell stemness, hypoxic response, glucose metabolism, angiogenesis, and modulation of tumor-infiltrating lymphocytes (TILs) in the tumor microenvironment. P4HA1 is thus an attractive target for developing novel targeted therapies to improve treatment response in many cancer types.