Epigenetically regulated therapeutic intervention of cancer is
an emerging era of research in the development of a promising therapy.
Epigenetic changes are intrinsically reversible and providing the
driving force to drug resistance in colorectal cancer (CRC). The regulation
of polycomb group (PcG) proteins, BMI1 and EZH2, and the associated
CRC progression hold promises for a novel treatment regime. The present
study enlightens targeted photodynamic therapy (PDT) with potential
photosensitizer hypericin nanocomposite in the development of epigenetic-based
CRC therapy. We have synthesized hypericin-loaded transferrin nanoformulations
(HTfNPs) overcoming the compromised hydrophobicity and poor bioavailability
of the placebo drug. Targeted PDT with hypericin nanocomposite-induced
BMI1 degradation assisted CRC retardation. In the present study, transferrin
nanoparticles were reported to control the premature release of hypericin
and improve its availability with better targeting at the disease
site. Targeted intracellular internalization to colon cancer cells
having a differential expression of transferrin receptors, in vivo biodistribution, stability, and pharmacokinetics
provide promising applications in the nanodelivery system. Indeed, in vitro anticancer efficiency, cell cycle arrest at the
G0/G1 phase, and elevated reactive oxygen species (ROS) generation
confirm the anticancer effect of nanoformulation. In the exploration
of mechanism, nanotherapeutic intervention by activation of PP2A,
Caspase3 and inhibition of BMI1, EZH2, 3Pk, NFκB was evident.
An exciting outcome of this study uncovered the camouflaged role of
PP2A in the regulation of BMI1. PP2A mediates the ubiquitination/degradation
of BMI1, which is revealed by changes in the physical interaction
of PP2A and BMI1. Our study confirms the anticancer effect of HTfNP-assisted
PDT by inducing PP2A-mediated BMI1 ubiquitination/degradation demonstrating
an epigenetic-driven nanotherapeutic approach in CRC treatment.
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