A HIF-LIMD1 negative feedback mechanism mitigates the pro-tumorigenic effects of hypoxia

Foxler, DE, Bridge, KS, Foster, JG, Grevitt, P, Curry, S, Shah, KM, Davidson, KM, Nagano, A, Gadaleta, E, Rhys, HI, Kennedy, PT, Hermida, MA, Chang, T-Y, Shaw, PE, Reynolds, LE, McKay, T ORCID: https://orcid.org/0000-0002-9128-9115, Wang, H-W, Ribeiro, PS, Plevin, MJ, Lagos, D, Lemoine, NR, Rajan, P, Graham, TA, Chelala, C, Hodivala-Dilke, KM, Spendlove, I and Sharp, TV (2018) A HIF-LIMD1 negative feedback mechanism mitigates the pro-tumorigenic effects of hypoxia. EMBO molecular medicine, 10 (8). pp. 1-18. ISSN 1757-4676

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Abstract

The adaptive cellular response to low oxygen tensions is mediated by the hypoxia-inducible factors (HIFs), a family of heterodimeric transcription factors composed of HIF-α and HIF-β subunits. Prolonged HIF expression is a key contributor to cellular transformation, tumorigenesis and metastasis. As such, HIF degradation under hypoxic conditions is an essential homeostatic and tumour-suppressive mechanism. LIMD1 complexes with PHD2 and VHL in physiological oxygen levels (normoxia) to facilitate proteasomal degradation of the HIF-α subunit. Here, we identify LIMD1 as a HIF-1 target gene, which mediates a previously uncharacterised, negative regulatory feedback mechanism for hypoxic HIF-α degradation by modulating PHD2-LIMD1-VHL complex formation. Hypoxic induction of LIMD1 expression results in increased HIF-α protein degradation, inhibiting HIF-1 target gene expression, tumour growth and vascularisation. Furthermore, we report that copy number variation at the LIMD1 locus occurs in 47.1% of lung adenocarcinoma patients, correlates with enhanced expression of a HIF target gene signature and is a negative prognostic indicator. Taken together, our data open a new field of research into the aetiology, diagnosis and prognosis of LIMD1-negative lung cancers.