Salt-Inducible Kinases (SIKs) as Drivers of Hypoxic Adaptation in Liver Cancer

About the Project

Low oxygen (hypoxia) is a defining feature of many solid tumours, including hepatocellular carcinoma (HCC), and is strongly linked to aggressive behaviour and poor treatment response. Hypoxia forces cancer cells to reprogramme gene expression, metabolism and stress responses to survive in a hostile microenvironment. While hypoxia-inducible factors (HIFs) regulate many oxygen-responsive genes, it is increasingly clear that upstream signalling pathways controlling chromatin and transcription play a major role in shaping hypoxic cell states. These pathways are also attractive because, unlike transcription factors, they are directly druggable.

This PhD project builds on a kinase activity profiling array generated across a hypoxia (1% oxygen) time course (1, 6 and 24 hours) in two HCC cell lines (Huh7 and HepG2). From this unbiased screen, the Salt-Inducible Kinase (SIK) family (SIK1/2/3) emerged as highly activated during hypoxia. SIKs are AMPK-related serine/threonine kinases that regulate transcription and the chromatin landscape by phosphorylating key co-regulators, including CRTC proteins and class IIa histone deacetylases (HDACs), with downstream effects on chromatin organisation and gene expression. Despite strong biological plausibility and increasing pharmacological interest, the role of SIKs in hypoxia- and in HCC specifically- remains largely unexplored, offering significant discovery potential.

The student will define how SIK kinases contribute to hypoxic adaptation in HCC and whether SIK-dependent signalling establishes transcriptional and chromatin programmes that support survival, invasion and therapy resistance under low oxygen. The work will combine time-resolved signalling with mechanistic and functional approaches: (i) validating and mapping SIK activation during hypoxia using phospho-protein and phospho-substrate readouts alongside established hypoxia markers; (ii) establishing causality using isoform-resolved genetics (siRNA/CRISPR with rescue by wild-type versus kinase-dead constructs) and commercially available SIK inhibitors, coupled to targeted gene panels and RNA-seq; (iii) defining mechanism by tracking co-regulator localisation and measuring hypoxia-dependent chromatin accessibility (e.g., ATAC-seq and/or targeted chromatin assays); and (iv) linking molecular mechanisms to clinically relevant phenotypes under hypoxia and hypoxia–reoxygenation, including survival/clonogenic recovery, migration/invasion and response to standard HCC therapies.

The project offers training in modern cancer signalling, functional genomics and chromatin biology, while addressing a clinically important problem. By establishing a SIK-dependent hypoxia signalling axis in HCC, the work has potential to reveal new vulnerabilities of hypoxia-adapted tumour cells and generate a mechanistic rationale for future combination strategies to limit hypoxia-driven progression and treatment resistance.

Funding

Students who have, or are expecting to attain, at least an upper second-class honours degree (or equivalent) in a relevant subject, are invited to apply. Funding is available for Home (UK) students to cover tuition fees, a tax-free stipend at the UKRI rate (indicative amount in year 1 in 2026-27, £21,805) and research costs, for four years. Applicants normally required to cover International fees will have to cover the difference between the Home and the International tuition fee rates. There is no additional funding available to cover NHS Immigration Health Surcharge (IHS) costs, visa costs, flights etc.

Funding for this studentship is awarded on a competitive basis and is not guaranteed; availability will depend on the outcome of the selection process and subject to final approval by the University.