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Localisation of the Golgi pH regulator GPR89 extends to the endoplasmic reticulum and confers selective dependency in breast cancer

ABSTRACT: Identification of targetable biology in breast cancer is an important unmet need, particularly for triple negative breast cancer (TNBC) where outcomes are poor and there are few licensed targeted therapies. Here, we identify the anion channel GPR89 as a novel breast cancer oncogene relevant in TNBC and other subtypes. We demonstrate that GPR89 extends its usual localisation from the Golgi in non-malignant cells to Endoplasmic Reticulum (ER)/Golgi in breast cancer cells where it regulates ER pH. Extended localisation of GPR89, to include mitochondria-ER associated membranes (MAMs), is also associated with GPR89 dependency. We further demonstrate that GPR89 helps breast cancer cells survive ER stress through modulation of the unfolded protein response and helps support cancer cells to rewire their metabolism towards glycolysis by extending localisation to the MAMs. This suggests the GPR89 anion channel as a potential novel drug target relevant to aggressive breast cancers with limited targeted therapy options.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: James Wright

LAB HEAD: Jyoti Choudhary

PROVIDER: PXD031422 | Pride | 2026-06-02

REPOSITORIES: Pride

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			Action	DRS
	20181108_RF_Tutt_lab_LMS_set01_01.raw	Raw
	20181108_RF_Tutt_lab_LMS_set01_02.raw	Raw
	20181108_RF_Tutt_lab_LMS_set01_03.raw	Raw
	20181108_RF_Tutt_lab_LMS_set01_04.raw	Raw
	20181108_RF_Tutt_lab_LMS_set01_05.raw	Raw

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Project description:SEPN1 is a type II protein of the endoplasmic reticulum (ER) whose loss of function gives rise to a collection of debilitating autosomal recessive myopathies gathered under the umbrella term of SEPN1-related myopathy (RM). At the moment, SEPN1-RM lacks an effective pharmacological treatment; thus, the medical management of the disease is only supportive. The potentially fatal diaphragmatic weakness leading to respiratory insufficiency in patients still ambulant is the main reason for medical concerns. Thus, studies on SEPN1-RM pathogenesis are necessary to implement a targeted pharmacological therapy aimed at relieving the general muscle weakness and the more worrisome diaphragmatic dysfunction. Here, we show a physical and functional interaction between SEPN1 and the ER stress mediator ERO1 alpha (henceforth, ERO1). Both SEPN1 and ERO1 are involved in the redox regulation of proteins into the ER, although in an opposite way SEPN1 imposes a less oxidant ER poise while ERO1 a more oxidant one, conceivable with a reductase function of SEPN1 and an oxidase one of ERO1. Furthermore, both are mainly localized in a region of the ER in close contact with mitochondria termed mitochondria-associated membranes (MAMs) and their loss impacts oppositely on the short-range MAMs, thereby impinging ER-mitochondria Ca2+ dynamics, OXPHOS, and bioenergetics. We find that ERO1 depletion restores the impaired short-range MAMs due to SEPN1 loss together with mitochondrial ATP. ERO1 knockout in a mouse background of SEPN1 loss blunts ER stress and the consequent Unfolded Protein Response (UPR) while it rescues the diaphragmatic weakness by improving ER/mitochondria contacts, calcium dynamics, and OXPHOS. Importantly, treatments of SEPN1 knock out mice with the chemical chaperone tauroursodeoxycholic acid (TUDCA) mimic the results of ERO1 loss improving calcium dynamics, OXPHOS, ER/mitochondria contacts, thereby rescuing diaphragmatic weakness as well. In addition, TUDCA-treated SEPN1-RM patients-derived myoblasts show a dynamic dose-dependent increase in ATP levels under ER stress conditions suggesting improved mitochondrial function. Thus, our findings point to the ERO1 axis in the pathogenesis of SEPN1-RM thereby impinging on MAMs and mitochondria bioenergetics and recall for the efficacy of a pharmacology therapy with ad hoc ER stress/ERO1 inhibitors for SEPN1-RM.

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Localisation of the Golgi pH regulator GPR89 extends to the endoplasmic reticulum and confers selective dependency in breast cancer

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