Oral squamous cell carcinoma (OSCC) is amongst the most prevalent form of cancer worldwide
with its predominance in the Indian subcontinent due to its etiological behavioral pattern of tobacco consumption.
Late diagnosis, low therapeutic response and aggressive metastasis are the foremost confounders
accountable for the poor 5 year survival rate of OSCC. These failures are attributed to the existence of “Cancer
Stem cell (CSC)” subpopulation within the tumour environment. Quiescence, apoptotic evasion, resistance to DNA
damage, abnormal expression of drug transporter pumps and in vivo tumorigenesis are the defining hallmarks of CSC
phenotype. These CSCs have been distinguished from the tumor mass by determining the expression patterns of cell surface
proteins, specific stemness markers and quantifying the cellular activities such as drug efflux & aldehyde dehydrogenase
activity. Hence, it is necessary to understand the underlying mechanisms that regulate the CSC features in tumor
development, metastasis and response to chemotherapy. Increasing evidence suggests that majority of malignant cells
eventually undergoing Epithelial-Mesenchymal transition (EMT) share many biological characteristics with CSCs. Thus,
this review encompasses the functional relevance of CSC and EMT markers in OSCC population with a hope to elucidate
the fundamental mechanisms underlying cancer progression and to highlight the most relevant epigenetic mechanisms that
contribute to the regulation of CSC features. We further aimed to explore the causal effects of nicotine, a major tobacco
carcinogen, on epigenetic mechanisms regulating the OSCC CSCs and EMT markers which unravels the undisputable
contribution of tobacco in oral carcinogenesis.