CDCA4 Protein Complex Blocks Cellular Cleanup to Drive Lung Cancer Growth

Lung adenocarcinoma (LUAD) is the most common subtype of lung cancer, and identifying molecular drivers of its progression remains a critical research priority. This study focuses on CDCA4 (Cell Division Cycle-Associated Protein 4), a protein previously linked to LUAD development but whose role in mitochondrial quality control was unknown.

The researchers analyzed CDCA4 expression in clinical LUAD specimens and found it significantly elevated compared to adjacent non-cancerous tissue. Importantly, higher CDCA4 levels inversely correlated with mitophagy activity — the cellular housekeeping process that selectively degrades dysfunctional mitochondria via the PINK1/Parkin pathway.

Using lentiviral gene-silencing in established LUAD cell lines, the team showed that knocking down CDCA4 activated PINK1/Parkin-mediated mitophagy, increased mitochondrial superoxide levels, disrupted mitochondrial membrane potential, enhanced LC3-II conversion, and degraded mitochondrial membrane proteins — all hallmarks of mitophagy induction. Silencing CDCA4 also reduced cancer cell proliferation and migration, effects that were reversed by the lysosomal inhibitor chloroquine and worsened by the autophagy inducer rapamycin.

Mechanistically, CDCA4 was shown to physically interact with and stabilize the proteins SERTAD1 and E2F1. Overexpressing these partners blunted the pro-mitophagy effects of CDCA4 silencing, confirming the functional importance of the full complex. In vivo, mice implanted with CDCA4-silenced LUAD cells showed reduced tumor growth, increased apoptosis, and elevated mitophagy markers.

These findings establish the CDCA4/SERTAD1/E2F1 axis as a mitophagy-suppressing oncogenic hub in LUAD. While the work is largely preclinical, it opens avenues for targeted therapies designed to disrupt this complex and restore protective mitophagy in lung cancer patients.