Targeting transcriptional and post-transcriptional pathways in head and neck cancer

Head and neck cancer (HNC) is a molecularly heterogeneous group of multisite malignancies that arise through two major carcinogenic routes- first, chemical carcinogenesis associated with tobacco use and/or alcohol intake, and second, infection with oncogenic human papillomaviruses (HPVs) in a clinically distinct subset of HNCs. Unlike cervical cancer, where HPV infection is typically associated with aggressive invasive disease and poor prognosis, HPV-positive HNCs generally present a more favourable clinical outcome, particularly among non-tobacco users. Conversely, HPV-negative HNC patients who are predominantly tobacco and/or alcohol users, exhibit a poor prognosis and lower survival rate. Despite significant advances in treatment strategies for HNCs, therapy resistance leading to aggressive tumor recurrence and mortality remains to be a major clinical challenge. Transcription factors (TFs), as key regulators of gene expression and cellular signalling networks, play a critical role in head and neck carcinogenesis and represent promising targets for cancer therapy. A comprehensive understanding of the transcriptional and post-transcriptional/translational regulation of TFs, as well as the molecular mechanism(s) underlying their dual role as oncogenes or tumor suppressors, is essential for the development of effective therapies. This review focuses on major transcriptional regulators transcriptional regulators with establishd or emerging relevance in HNC pathobiology including AP-1, NF-κB, STAT3 MYC, SOX2, YY1, p53, p63 and NOTCH1. We discuss their oncogenic, tumor suppressive and context-dependent functions, with emphasis on how these factors coordinate downstream signalling networks during HNC development and progression, and therapeutic resistance. Overall, dysregulation of transcription factor in HNC is not limited to single pathway activation. Instead, TFs interact with non-coding RNAs and epigenetic mechanisms to form interconnected regulatory networks that promote both tumor plasticity and create potential therapeutic opportunities. Effective targeting of these networks will require biomarker-guided and rational combination strategies tailored to tumor type.