Survivin is a member of the inhibitor of apoptosis protein family that regulates cell proliferation and inhibition of apoptosis. While its cytoplasmic roles in apoptosis inhibition and mitotic regulation are well characterised, the nuclear functions of survivin remain poorly understood. Emerging evidence suggests that nuclear localisation of survivin may hold critical significance for tumour progression as elevated nuclear survivin levels have been correlated with poor prognosis in cancer patients across multiple tumour types, as well as aggressive tumour phenotypes, yet the mechanistic basis for these clinical observations remains unclear. We hypothesised that nuclear survivin directly influences transcriptional processes to enhance cell survival. We examined survivin expression under conditions mimicking the tumour microenvironment, such as hypoxia, DNA damage, and serum starvation. Our imaging and subcellular fractionation studies demonstrate that survivin translocates from the cytoplasm to the nucleus under stress conditions. To elucidate its nuclear functions, we used GST pull-down and co-immunoprecipitation assays to identify survivin-binding partners, demonstrating that its BIR domain is crucial for facilitating interactions with the key transcription factor STAT3 and the PRC2 complex. Interestingly the latter occurs via EZH2, the catalytic subunit of the complex and leads to derepression of PRC2 target genes. Beyond its nuclear role, we identified a novel interaction between survivin and the mitochondrial apoptotic regulators, VDAC, BCL-XL, and BAX. This complex suggests a new mechanism by which survivin directly modulates mitochondrial apoptosis and inhibits cytochrome c release. Collectively, our findings establish a dual-function model for survivin: a nuclear modulator of transcriptional activity, and a direct regulator of the mitochondrial apoptotic machinery. These newly identified roles provide a more comprehensive understanding of how survivin confers a survival advantage and suggest new therapeutic opportunities for targeting this critical protein in cancer.
Adesh D. Vaidya (Thu,) studied this question.